Isothiourea derivatives or isourea derivatives having bace1 inhibitory activity

ABSTRACT

The present invention provides, for example, a compound of the following formula (I): 
     
       
         
         
             
             
         
       
         
         wherein R 1  is substituted amino and the like, 
         R 2  is halogen and the like, 
         R 3  is substituted or unsubstituted lower alkyl and the like, 
         R A  and R B  are each independently hydrogen, substituted or unsubstituted lower alkyl and the like, 
         R C  and R D  are each independently hydrogen, substituted or unsubstituted lower alkyl, or R C  and R D  together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle, and 
         ring A is a carbocycle or a heterocycle, 
         its pharmaceutically acceptable salt, or a solvate thereof as a therapeutic agent for diseases induced by production, secretion and/or deposition of amyloid-βproteins.

TECHNICAL FIELD

The present invention relates to a compound having an effect ofinhibiting amyloid-β production and is useful as a therapeutic agent fordiseases induced by production, secretion and/or deposition of amyloid-βproteins.

BACKGROUND ART

In the brains of patients with Alzheimer's disease, peptides eachconsisting of approximately 40 amino acids, called amyloid-β proteins,which widely accumulate outside neurons to form insoluble plaques(senile plaques) are observed. These senile plaques are thought to killneurons and cause the onset of Alzheimer's disease. As therapeuticagents for Alzheimer's disease, agents promoting degradation ofamyloid-β proteins and amyloid-β vaccines have been studied.

Secretases are enzymes which cleave a protein called amyloid-β precursorprotein (APP) within a cell and generate an amyloid-β protein. An enzymewhich produces N-terminals of amyloid-β proteins is called as BACE1(beta-site APP-cleaving enzyme 1, β-secretase). It is considered thatproduction of amyloid-β proteins may be suppressed by inhibiting thisenzyme, and thus a substance with such an effect can serve as atherapeutic agent for Alzheimer's disease.

Patent Documents 1 to 16 etc. disclose BACE1 inhibitors, but each ofthese compounds has a structure different from those of the compounds ofthe present invention.

Patent Documents 17 to 19, and Non-Patent Document 1 disclose compoundshaving a structure similar to those of the compounds of the presentinvention. Each of these document discloses each of these compound isuseful as a therapeutic agent for neurological diseases or NOS inhibitorand the like.

PRIOR ART Patent Document

-   Patent Document 1: WO2007/049532 pamphlet-   Patent Document 2: WO2008/133274 pamphlet-   Patent Document 3: WO2008/133273 pamphlet-   Patent Document 4: WO2009/151098 pamphlet-   Patent Document 5: US2006/0183790-   Patent Document 6: US2006/0183792-   Patent Document 7: US2006/0183943-   Patent Document 8: WO02/96897 pamphlet-   Patent Document 9: WO04/043916 pamphlet-   Patent Document 10: WO2005/058311 pamphlet-   Patent Document 11: WO2005/097767 pamphlet-   Patent Document 12: WO2006/041404 pamphlet-   Patent Document 13: WO2006/041405 pamphlet-   Patent Document 14: US2007/0004786-   Patent Document 15: US2007/0004730-   Patent Document 16: US2007/27199-   Patent Document 17: WO95/09619 pamphlet-   Patent Document 18: WO94/12165 pamphlet-   Patent Document 19: WO96/18608 pamphlet

Non-Patent Document

-   Non-Patent Document 1: Bioorg. Med. Chem. 4189, 11, (2003)

SUMMARY OF THE INVENTION The Problems to be Solved by the Invention

The present invention provides a compound which has an effect ofinhibiting amyloid-β production, in particular a BACE1 inhibitoryeffect, and is useful as a therapeutic agent for diseases induced byproduction, secretion or deposition of amyloid-β proteins.

Means to Solve the Problems

The present invention provides:

1) A compound of formula (I):

wherein X is an oxygen atom or a sulfur atom,ring A is a carbocycle or a heterocycle,(1) when X is an oxygen atom,R¹ is substituted amino, provided that substituted amino is notimino(phenoxy)methylamino or imino(lower alkoxy)methylamino; substitutedor unsubstituted mercapto; substituted or unsubstituted carbocyclyl; orsubstituted or unsubstituted heterocyclyl;and R¹ may be hydrogen when ring A is naphthalene,(2) when X is a sulfur atom,R¹ is substituted or unsubstituted acylamino, provided that “substitutedor unsubstituted acylamino” is not unsubstituted acetylamino orunsubstituted benzoylamino; substituted or unsubstitutedhalogenosulfonylamino; substituted or unsubstituted loweralkylsulfonylamino; substituted or unsubstituted loweralkenylsulfonylamino; substituted or unsubstituted loweralkynylsulfonylamino; substituted or unsubstituted acylsulfonylamino;substituted or unsubstituted carbocyclylsulfonylamino; substituted orunsubstituted heterocyclylsulfonylamino; substituted or unsubstitutedmercapto; substituted or unsubstituted carbocyclyl; or substituted orunsubstituted heterocyclyl, provided that “substituted or unsubstitutedheterocyclyl” is not thiazolyl substituted with unsubstitutedacetylamino;and R¹ may be hydrogen when ring A is naphthalene,R² is halogen, substituted or unsubstituted hydroxy, substituted orunsubstituted mercapto, substituted or unsubstituted amino, substitutedor unsubstituted lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkynyl, substituted orunsubstituted acyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl,R³ is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl,R^(A) and R^(B) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted acyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, orR^(A) and R^(B) taken together may form oxo, or R^(A) and R^(B) togetherwith the carbon atom to which they are attached may form a substitutedor unsubstituted carbocycle or a substituted or unsubstitutedheterocycle,R^(C) and R^(D) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted acyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, orR^(C) and R^(D) together with the carbon atom to which they are attachedmay form a substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle,m is an integer of 0 to 2,n is an integer of 0 to 4, andp is an integer of 0 to 2,its pharmaceutically acceptable salt, or a solvate thereof.1′) A compound of formula

whereinX is a sulfur atom or an oxygen atom,ring A is a heterocycle or a carbocycle,R¹ is substituted amino, provided that (i) when X is a sulfur atom, thenthe substituent is not unsubstituted lower alkoxycarbonyl,imino(substituted mercapto)methyl or substituted 1,3,5-triazin-2-yl, and(ii) when X is an oxygen atom, then the substituent is notimino(phenoxy)methyl, imino(methoxy)methy or imino(ethoxy)methyl;substituted or unsubstituted mercapto; substituted or unsubstitutedcycloalkyl; substituted or unsubstituted aryl; or substituted orunsubstituted heterocyclyl, provided that when X is a sulfur atom, thensubstituted or unsubstituted heterocyclyl is not thiazolyl substitutedwith acetylamino, andR¹ may be hydrogen when ring A is naphthalene,R² is halogen, substituted or unsubstituted hydroxy, substituted orunsubstituted mercapto, substituted or unsubstituted amino, substitutedor unsubstituted lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted acyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heterocyclyl,R³ is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted aryl, or substituted orunsubstituted heterocyclyl,R^(A) and R^(B) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedacyl, substituted or unsubstituted aryl or substituted or unsubstitutedheterocyclyl, orR^(A) and R^(B) taken together may form oxo, orR^(A) and R^(B) together with the carbon atom to which they are attachedmay form a substituted or unsubstituted carbocycle,R^(C) and R^(D) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedacyl, substituted or unsubstituted aryl, or substituted or unsubstitutedheterocyclyl, orR^(C) and R^(D) together with the carbon atom to which they are attachedmay form a substituted or unsubstituted carbocycle,m is an integer of 0 to 2,n is an integer of 0 to 4, andp is an integer of 0 to 2,its pharmaceutically acceptable salt, or a solvate thereof,1″) The compound of formula (I):

wherein R¹ is substituted amino, provided that the substituent of“amino” is not unsubstituted lower alkoxycarbonyl, imino(substitutedmercapto)methyl or substituted 1,3,5-triazine-2-yl; substituted orunsubstituted mercapto; substituted or unsubstituted cycloalkyl;substituted or unsubstituted aryl; or substituted or unsubstitutedheterocyclyl, provided that “substituted or unsubstituted heterocyclyl”is not thiazolyl substituted with acetylamino; andR² is halogen, substituted or unsubstituted hydroxy, substituted orunsubstituted mercapto, substituted or unsubstituted amino, substitutedor unsubstituted lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted acyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heterocyclyl,R³ is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted aryl, or substituted orunsubstituted heterocyclyl,R^(A) and R^(B) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedacyl, substituted or unsubstituted aryl, or substituted or unsubstitutedheterocyclyl, orR^(A) and R^(B) taken together may form oxo, orR^(A) and R^(B) together with the carbon atom to which they are attachedmay form a substituted or unsubstituted carbocycle,R^(C) and R^(D) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedacyl, substituted or unsubstituted aryl, or substituted or unsubstitutedheterocyclyl, orR^(C) and R^(D) together with the carbon atom to which they are attachedmay form a substituted or unsubstituted carbocycle,ring A is a heterocycle or a carbocycle,X is a sulfur atom or an oxygen atom,m is an integer of 0 to 2,n is an integer of 0 to 4, andp is an integer of 0 to 2, provided that when ring A is a monocycle,then p is not 0, its pharmaceutically acceptable salt, or a solvatethereof.2) The compound according to any one of the above 1), 1′) or 1″) wherein(1) when X is an oxygen atom, R¹ is substituted amino, provided that“substituted amino” is not imino(phenoxy)methylamino or imino(loweralkoxy)methylamino; substituted or unsubstituted mercapto; substitutedor unsubstituted cycloalkyl; substituted or unsubstituted aryl; orsubstituted or unsubstituted heterocyclyl; and(2) when X is a sulfur atom, R¹ is substituted or unsubstitutedacylamino, provided that “substituted or unsubstituted acylamino” is notunsubstituted acetylamino or unsubstituted benzoylamino; substituted orunsubstituted halogenosulfonylamino; substituted or unsubstituted loweralkylsulfonylamino; substituted or unsubstituted loweralkenylsulfonylamino; substituted or unsubstituted loweralkynylsulfonylamino; substituted or unsubstituted acylsulfonylamino;substituted or unsubstituted carbocyclylsulfonylamino; substituted orunsubstituted heterocyclylsulfonylamino; substituted or unsubstitutedmercapto; substituted or unsubstituted cycloalkyl; substituted orunsubstituted aryl or substituted or unsubstituted heterocyclyl,provided that “substituted or unsubstituted heterocyclyl” is notthiazolyl substituted with unsubstituted acetylamino; itspharmaceutically acceptable salt, or a solvate thereof2′) The compound according to any one of the above 1), 1′) or 1″)whereinR¹ is substituted amino, provided that (i) when X is a sulfur atom, thenthe substituent is not unsubstituted lower alkoxycarbonyl,imino(substituted mercapto)methyl or substituted 1,3,5-triazin-2-yl; and(ii) when X is an oxygen atom, then the substituent is notimino(phenoxy)methyl, imino(methoxy)methyl or imino(ethoxy)methyl);substituted or unsubstituted mercapto; substituted or unsubstitutedcycloalkyl;substituted or unsubstituted aryl; or substituted or unsubstitutedheterocyclyl, provided that when X is a sulfur atom, then “substitutedor unsubstituted heterocyclyl” is not thiazolyl substituted withacetylamino;its pharmaceutically acceptable salt, or a solvate thereof.3) The compound according to any one of the above 1), 1′), 1″), 2) or2″) wherein ring A is an aromatic carbocycle or an aromatic heterocycle,m is an integer of 0,R¹ is substituted or unsubstituted acylamino, provided that when X is asulfur atom, then “substituted or unsubstituted” acylamino is notunsubstituted acetylamino or unsubstituted benzoylamino; andR² is halogen, substituted or unsubstituted hydroxy, substituted orunsubstituted mercapto, substituted or unsubstituted amino, substitutedor unsubstituted lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkynyl, substituted orunsubstituted acyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl,its pharmaceutically acceptable salt or a solvate thereof4) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3), wherein X is an oxygen atom, its pharmaceutically acceptable saltor a solvate thereof.5) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3), wherein X is a sulfur atom, its pharmaceutically acceptable saltor a solvate thereof.6) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 5) wherein ring A is a monocycle and p is 1 or 2, or (ii) ringA is a fused ring and p is 0, its pharmaceutically acceptable salt or asolvate thereof.7) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 6) wherein ring A is a benzene ring or a benzene ring fusedwith another ring, its pharmaceutically acceptable salt or a solvatethereof.7′) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 6) wherein the formula:

is

wherein R¹, R², R^(A), R^(B), R^(C), R^(D), m, n and p is the same asdefined in the above 1), and ring B is a carbocycle.8) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 7) wherein R¹ is substituted or unsubstituted acylamino,provided that when X is a sulfur atom, then “substituted orunsubstituted acylamino” is not unsubstituted acetylamino orunsubstituted benzoylamino; substituted or unsubstitutedhalogenosulfonylamino; substituted or unsubstituted loweralkylsulfonylamino; substituted or unsubstituted loweralkenylsulfonylamino; substituted or unsubstituted loweralkynylsulfonylamino; substituted or unsubstituted acylsulfonylamino;substituted or unsubstituted carbocyclylsulfonylamino; substituted orunsubstituted heterocyclylsulfonylamino; or substituted or unsubstitutedaryl; its pharmaceutically acceptable salt or a solvate thereof.9) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 8) wherein R¹ is substituted or unsubstituted acylamino,provided that when X is a sulfur atom, then “substituted orunsubstituted acylamino” is not unsubstituted acetylamino orunsubstituted benzoylamino; or substituted or unsubstituted loweralkylsulfonylamino; its pharmaceutically acceptable salt or a solvatethereof.10) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 9) wherein m is an integer of 0, its pharmaceuticallyacceptable salt or a solvate thereof,11) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 10) wherein R² is halogen and n is an integer of 0 or 1, itspharmaceutically acceptable salt or a solvate thereof.12) The compound according to any one of the above the above 1), 1′),1″), 2), 2′) or 3) to 11) wherein R² is substituted or unsubstitutedlower alkyl or substituted or unsubstituted lower alkenyl, itspharmaceutically acceptable salt or a solvate thereof.13) The compound according to any one of the above 1), 1′), 1″), 2), 2′)or 3) to 12) wherein R^(C) and R^(D) are each independently hydrogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedaryl or substituted or unsubstituted heterocyclyl, or R^(C) and R^(D)together with the carbon atom to which they are attached may form asubstituted or unsubstituted carbocycle, and p is an integer of 1, itspharmaceutically acceptable salt or a solvate thereof.13′) The compound according to the above 4) wherein m is an integer of0, R¹ is amino substituted with substituted or unsubstituted acyl, itspharmaceutically acceptable salt or a solvate thereof.13″) The compound according to the above 5) or 6) wherein ring A is abenzene ring, R¹ is substituted amino, substituted or unsubstitutedmercapto, substituted or unsubstituted aryl, or substituted orunsubstituted heterocyclyl, and p is an integer of 1 or 2, itspharmaceutically acceptable salt or a solvate thereof.14) A compound of formula (II):

wherein ring A is a carbocycle or a heterocycle,R⁵ is hydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynylor substituted or unsubstituted acyl,R⁴ is substituted or unsubstituted lower alkyl, provided that when X isa sulfur atom, then “substituted or unsubstituted lower alkyl” is notunsubstituted methyl; substituted or unsubstituted lower alkenyl; asubstituted, or unsubstituted carbocycle, provided that when X is asulfur atom, then “a substituted or unsubstituted carbocycle” is notunsubstituted phenyl; or a substituted or unsubstituted heterocycle;R² is halogen, substituted or unsubstituted hydroxy, substituted orunsubstituted mercapto, substituted or unsubstituted amino, substitutedor unsubstituted lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkynyl, substituted orunsubstituted acyl, substituted or unsubstituted carbocyclyl orsubstituted or unsubstituted heterocyclyl,R³ is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted carbocyclyl or substituted or unsubstitutedheterocyclyl,R^(C) and R^(D) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted acyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, or R^(C) and R^(D) together with the carbonatom to which they are attached may form a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle,n is an integer of 0 to 4, andp is an integer of 0 to 2,its pharmaceutically acceptable salt or a solvate thereof,15) The compound according to the above 14) wherein R⁴ is a substitutedor unsubstituted aromatic heterocycle or a substituted or unsubstitutedaromatic carbocycle, its pharmaceutically acceptable salt or a solvatethereof.16) The compound according to the above 14) or 15) wherein ring A is amonocycle, and R⁴ is a substituted or unsubstituted nitrogen-containingheterocycle, its pharmaceutically acceptable salt or a solvate thereof.17) A pharmaceutical composition comprising the compound according toany one of the above 1), 1′), 1″), 2), 2′), or 3) to 16), itspharmaceutically acceptable salt or a solvate thereof.18) A pharmaceutical composition having BACE1 inhibitory activitycomprising the compound according to any one of the above 1), 1′), 1″),2), 2′), or 3) to 16), its pharmaceutically acceptable salt or a solvatethereof.19) A pharmaceutical composition having amyloid B production inhibitoryactivity comprising the compound according to any one of the above 1),1′), 1″), 2), 2′), or 3) to 16), its pharmaceutically acceptable salt ora solvate thereof.20) A method for inhibiting BACE1 activity comprising administering thecompound according to any one of the above 1), 1′), 1″), 2), 2′), or 3)to 16), its pharmaceutically acceptable salt or a solvate thereof.21) A compound according to any one of the above 1), 1′), 1″), 2), 2′),or 3) to 16), its pharmaceutically acceptable salt or a solvate thereoffor use in a method for inhibiting BACE1 activity.22) A method for inhibiting amyloid B production comprisingadministering the compound according to any one of the above 1), 1′),1″), 2), 2′), or 3) to 16), its pharmaceutically acceptable salt or asolvate thereof.23) A compound according to any one of the above 1), 1′), I″), 2), 2′),or 3) to 16), its pharmaceutically acceptable salt or a solvate thereoffor use in a method for inhibiting amyloid β production.

23′) Use of the compound according to any one of the above 1), 1′), 1″),2), 2′), or 3) to 16), its pharmaceutically acceptable salt or a solvatethereof in the manufacture of a medicament for inhibiting amyloid Bproduction.

24) A method for treating diseases induced by production, secretion ordeposition of amyloid-β proteins comprising administering the compoundaccording to any one of the above 1), 1′), 1″), 2), 2′), or 3) to 16) ora pharmaceutically acceptable salt or a solvate thereof.25) A compound according to any one of the above 1), 1′), 1″), 2), 2′),or 3) to 16) or a pharmaceutically acceptable salt or a solvate thereoffor use in a method for treating diseases induced by production,secretion or deposition of amyloid-β proteins.25′) Use of the compound according to any one of the above 1), 1′), 1″),2), 2′), or 3) to 16) or a pharmaceutically acceptable salt or a solvatethereof in the manufacture of a medicament for treating diseases inducedby production, secretion or deposition of amyloid-β proteins.26) A method for treating Alzheimer's disease comprising administeringthe compound according to any one of the above 1), 1′), 1″), 2), 2′), or3) to 16) or a pharmaceutically acceptable salt or a solvate thereof.27) A compound according to any one of the above 1), 1′), 1″), 2), 2′),or 3) to 16) or a pharmaceutically acceptable salt or a solvate thereoffor use in a method for treating Alzheimer's disease.27′) Use of the compound according to any one of the above 1), 1′), 1″),2), 2′), or 3) to 16) or a pharmaceutically acceptable salt or a solvatethereof in the manufacture of a medicament for treating Alzheimer'sdisease.

Effect of Invention

The compound for the present invention is useful as a therapeutic agentfor diseases induced by production, secretion or deposition of amyloid-βproteins (e.g. Alzheimer's disease).

MODES FOR CARRYING OUT THE INVENTION

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine.

The halogen portions in “halogenosulfonyl” and “halogenosulfonylamino”are as defined above for the “halogen.”

The term “lower alkyl” as used herein includes C1-C15, preferablyC1-C10, more preferably C1-C6, and further preferably C1-C3 linear orbranched alkyl. Examples thereof include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl,isooctyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl,n-tetradecyl and n-pentadecyl.

The lower alkyl portions in “lower alkoxy”, “hydroxy lower alkoxy”,“lower alkoxy lower alkoxy”, “lower alkoxy acylamino”, “loweralkoxycarbonyl”, “lower alkyl alcohol”, “lower alkylsulfonyl”, “loweralkylthio”, “lower alkylamino”, “lower alkylsulfonyl amino”, “loweralkoxy imino”, “lower alkylthio”, “lower alkylcarbamoyl”, “hydroxy loweralkylcarbamoyl”, “lower alkysulfamoyl”, “lower alkylsulfinyl” and “iminolower alkoxymethyl” are as defined above for the “lower alkyl.”

Examples of the substituent of the “substituted or unsubstituted loweralkyl” are the substituent selected from the following Subsituent Groupα. The term “substituted alkyl” includes alkyl substituted with one ormore selected from the Substituent Group α.

The Substituent Group α herein consists of halogen, carboxy, loweralkoxycarbonyl, hydroxy optionally substituted with one or more selectedfrom the Substituent Group β, amino optionally substituted with one ormore selected from the Substituent Group β, acylamino optionallysubstituted with one or more selected from the Substituent Group γ,imino optionally substituted with one or more selected from theSubstituent Group β, mercapto optionally substituted with one or moreselected from the Substituent Group β, sulfamoyl, lower alkylsulfamoyl,lower alkylsulfinyl, lower alkylsulfonyl, lower alkenylsulfamoyl,loweralkenylsulfinyl, lower alkenylsulfonyl, lower alkynylsulfamoyl,lower alkynylsulfinyl, lower alkynylsulfonyl, acyl, cyano, nitro, oxo,carbocyclyl optionally substituted with one or more selected from theSubstituent Group γ, and heterocyclyl optionally substituted with one ormore selected from the Substituent Group γ.

The Substituent Group β herein consists of halogen, lower alkyl, loweralkenyl, lower alkynyl, cyano, carbocyclyl optionally substituted withone or more selected from the Substituent Group γ, and heterocyclyloptionally substituted with one or more selected from the SubstituentGroup γ.

The Substituent Group γ herein consists of halogen, hydroxy, loweralkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy lower alkoxy,lower alkoxy lower alkoxy, lower alkenyloxy, lower alkynyloxy, acyl,acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, loweralkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio,carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl,sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, loweralkylsulfonyl, cyano, nitro, carbocyclyl and heterocyclyl.

The substituents of “substituted or unsubstituted loweralkylsulfonylamino” are the same as those of “substituted orunsubstituted lower alkyl.”

The term “lower alkenyl” as used herein includes linear or branchedC2-C15, preferably C2-C10, more preferably C2-C6, more preferably C2-C4alkenyl having one or more double bonds at optional positions. Examplesinclude vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl,prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl and pentadecenyl.

The term “lower alkynyl” as used herein includes straight or branchedC2-C10, preferably C2-C8, more preferably C3-C6 alkynyl having one ormore triple bonds at optional positions. Examples include ethynyl,propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl anddecynyl. These may further a double bond at an optional position.

Examples of the substituent of “substituted or unsubstituted loweralkenyl” and “substituted or unsubstituted lower alkynyl” include one ormore selected from the above Substituent Group α. The terms “substitutedalkenyl” and “substituted alkynyl” as used herein include alkenyl andalkynyl, each of which is substituted with one or more selected fromSubstituent Group α.

The lower alkenyl portions in “lower alkenylsulfonyl”, “loweralkenyloxy”, “lower alkenyloxy acylamino”, “lower alkenylamino”, “loweralkenylsulfonylamino”, “lower alkenylsulfamoyl” and “loweralkenylsulfinyl” are as defined above for the “lower alkenyl.”

The lower alkynyl portions in “lower alkynyloxy”, “lower alkynyloxy acylamino”, “lower alkynylamino”, “lower alkynylsulfonyl”, “loweralkynylsulfonylamino”, “lower alkynylsulfamoyl” and “loweralkynylsulfinyl” are as defined above for the “lower alkynyl.”

The substituents of “substituted or unsubstituted loweralkenylsulfonylamino” and “substituted or unsubstituted loweralkynylsulfonylamino” are the same as those of “substituted orunsubstituted lower alkenyl” and “substituted or unsubstituted loweralkynyl.”

Examples of substituents of “substituted or unsubstituted hydroxy”,“substituted mercapto”, “substituted or unsubstituted mercapto”,“substituted amino” and “substituted or unsubstituted amino” includesubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted lower alkynyl, substitutedor unsubstituted acyl, substituted or unsubstituted loweralkoxycarbonyl, substituted or unsubstituted halogenosulfonyl,substituted or unsubstituted lower alkylsulfonyl, substituted orunsubstituted lower alkenyl sulfonyl, substituted or unsubstituted loweralkynylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl,substituted or unsubstituted cycloalkenylsulfonyl, substituted orunsubstituted acylsulfonyl, substituted or unsubstituted arylsulfonyl,substituted or unsubstituted heterocyclylsulfonyl, substituted orunsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl.“Substituted or unsubstituted hydroxy”, “substituted mercapto”,“substituted or unsubstituted mercapto”, “substituted amino” and“substituted or unsubstituted amino” can be optionally substituted with1 to 2 groups selected from the above.

The amino portions in “substituted or unsubstituted acylamino”,“substituted or unsubstituted halogenosulfonylamino”, “substituted orunsubstituted lower alkylsulfonylamino”, “substituted or unsubstitutedlower alkenylsulfonylamino”, “substituted or unsubstituted loweralkynylsulfonylamino”, “substituted or unsubstituted cycloalkylsulfonylamino”, “substituted or unsubstituted cycloalkenylsulfonylamino”, “substituted or unsubstituted acylsulfonylamino”,“substituted or unsubstituted arylsulfonylamino” and “substituted orunsubstituted heterocyclylsulfonyla” may be further substituted with agroup selected from the following groups.

Lower alkyl optionally substituted with one or more selected fromSubstituent Group α, lower alkenyl optionally substituted with one ormore selected from Substituent Group α, lower alkynyl optionallysubstituted with one or more selected from Substituent Group α, acyloptionally substituted with one or more selected from Substituent Groupα, carboxy, lower alkoxycarbonyl, hydroxy optionally substituted withone or more selected from Substituent Group β, amino optionallysubstituted with one or more selected from Substituent Group β,acylamino optionally substituted with one or more selected fromSubstituent Group γ, mercapto optionally substituted with one or moreselected from Substituent Group β, sulfamoyl, lower alkylsulfamoyl,lower alkylsulfinyl, lower alkylsulfonyl, lower alkenylsulfamoyl, loweralkynylsulfinyl, lower alkenylsulfonyl, lower alkynylsulfamoyl, loweralkynylsulfinyl, lower alkynylsulfonyl, acyl, cyano, carbocyclyloptionally substituted with one or more selected from Substituent Groupγ, and heterocyclyl optionally substituted with one or more selectedfrom Substituent Group γ.

The term “acyl” as used herein includes C1-C10 aliphatic acyl,carbocyclylcarbonyl and heterocyclylcarbonyl. Examples include formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl,acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl,cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl,benzothiazolecarbonyl, pyrazinecarbonyl, piperidinecarbonyl andthiomorpholino.

The acyl portions in “acylamino”, “lower alkoxy acylamino”, “loweralkenyloxy acylamino”, “lower alkynyloxy acylamino”, “acylsulfonyl” and“acylsulfonylamino” are as defined above.

Examples of the substituent of the “substituted or unsubstituted acyl”include the substituent selected from the above Substitutent Group α.The term “substituted acyl” include acyl substituted with one or moreselected from Substituent Group α. The ring portions incarbocyclylcarbonyl and heterocyclylcarbonyl may be substituted with oneor more selected from the group of (i) lower alkyl optionallysubstituted with one or more selected from Substituent Group α, (ii)lower alkenyl optionally substituted with one or more selected fromSubstituent Group α, (iii) lower alkynyl'optionally substituted with oneor more selected from Substituent Group α, and (iv) Substituent Group α.

The substituents of “substituted or unsubstituted acylamino” and“substituted or unsubstituted acylsulfonylamino” are the same as thoseof “substituted or unsubstituted acyl”

The term “carbocycle” as used herein includes C3-C10 cycloalkane, C3-C10cycloalkene, aromatic carbocycle and non-aromatic fused carbocycle. Thecarbocycle portions in “carbocyclylcarbonyl” and“carbocyclylsulfonylamino” are the same as the above “carbocycle.”

The term “carbocyclyl” as used herein includes cycloalkyl, cycloalkenyl,aryl and non-aromatic fused carbocyclyl.

The term “cycloalkane” includes C3-C10, preferably C3-C8, and morepreferably C4-C8 carbocycle. Examples are cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane andcyclohexane.

The term “cycloalkyl” as used herein includes C3-C10, preferably C3-C8,and more preferably C4-C8 carbocyclyl. Examples are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyland cyclodecyl.

The cycloalkyl portions in “cycloalkylsulfonyl” and“cycloalkylsulfonylamino” are as defined for the “cycloalkyl.”

The term “cycloalkene” as used herein includes a ring of the above“cycloalkane” having one or more double bonds at optional positions suchas cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene,cyclooctene and cyclohexadiene.

The term “cycloalkenyl” as used herein includes a ring of the above“cycloalkyl” having one or more double bonds at optional positions suchas cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl and cyclohexadienyl.

The cycloalkenyl portion in “cycloalkenylsulfonyl” and“cycloalkonylsulfonylamino” are as defined above for the “cycloalkenyl.”

The term “aromatic carbocycle” as used herein includes C6-C14,preferably C6-C10, more preferably C6 carbocycle and examples are abenzene ring, a nap htharene ring, an anthracene ring, and aphenanthrene ring. Specific example is a benzene ring.

The term “aryl” as used herein includes phenyl, naphthyl, anthryl andphenanthryl. Specific example is phenyl.

The aryl portions in “arylsulfonyl” and “arylsulfonylamino” are asdefined for the “aryl.”

The term as used herein “non-aromatic fused carbocycle” includes fusedrings comprising two or more rings, each of ring is selected from thegroup of “cycloalkane”, “cycloalkene” and “aromatic carbocycle”, and atleast one ring is “cycloalkane” or “cycloalkene.” Examples are indane,indene and fluorine.

The term as used herein “non-aromatic fused carbocyclyl” include amonovalent group derived by eliminating a hydrogen atom from the ring ofthe “non-aromatic fused carbocycle” such as indenyl, indenyl andfluorenyl.

The phrase as used herein “together with the carbon atom to which theyare attached may form a carbocycle” includes the “carbocycle” which isformed by two substituents and the carbon atom to which the substituentsare attached such as

wherein either one of bonds indicated by a and b bonds to ring A,

The phrase as used herein “together with the carbon atom to which theyare attached may form a substituted or unsubstituted carbocycle”includes the carbocycle optionally substituted with the after-mentionedsubstituents for “substituted or unsubstituted carbocycle.”

The term as used herein “heterocyclyl” includes heterocyclyl having oneor more hetero atoms arbitrarily selected from O, S and N in the ring.Specific examples thereof include 5 to 6-membered monocyclic heteroarylsuch as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, andthiadiazolyl; 5- to 6-membered monocyclic non-aromatic heterocyclyl suchas dioxanyl, thiiranyl, oxyranyl, oxetanyl, oxathiolanyl, azetidinyl,thienyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl,dthydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl,dihydrooxazinyl, hexahydroazepinyl, tetrahydroazepinyl, andtetrahydropyridazinyl;

fused bicyclic heterocyclic groups such as indolyl, isoindolyl,indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisooxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl,imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl,pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl,naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxynyl, dihydrobenzooxezinyl, dihydrobenzodioxepinyl anddihydrothienodioxynyl; fused tricyclic heterocyclyl such as carbazolyl,acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,dibenzofuryl, imidazoquinolyl and tetrahydrocarbazolyl. Preferableexamples are 5 to 6-membered monocyclic heteroaryl or non-aromaticheterocyclyl.

The term as used herein “heterocycle” is a cyclic structure which is aconstituent of the “heterocyclyl.”

The heterocyclyl portions in “heterocyclylsulfonyl”,“heterocyclylsulfonylamino” and “heterocyclylcarbonyl” are as definedabove for the “heterocyclyl.”

The term as used herein “aromatic heterocycle” includes aromatic ringsin a cyclic structure which is a constituent of the “heterocyclyl.”Examples are pyrrole, imidazole, pyrazole, pyridine, pyridazine,pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophen,isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole,indole, isoindole, indazole, indolizine, indoline, isoindoline,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,naphthyridine, quinoxalome, purine, pteridine, benzimidazole,benzotriazole, benzisooxazole, benzoxazole, benzoxadiazole,benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran,isobenzofuran, benzothiophen, benzotriazole, thienopyridine,thienopyrrole, thienopyrazole, thienopyrazine, furopyrrole,thienothiophen, imidazopyridine, pyrazolopyridine, thiazolopyridine,pyrazolopyrimidine, pyrazolotriazine, pyridazolopyridine,triazolopyridine, imidazothiazole and pyrazinopyridazine.

The term as used herein “nitrogen-containing heterocycle” includes ringswhich contain one or more nitrogen atoms in the above “heterocycle” suchas pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine,pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole,isothiazole, thiazole, thiadiazole, pyrrolidine, pyrroline,imidazolidine, imidazone, pyrazolidine, pyrazoline, piperidine,piperazine, morpholine, thiomorpholine, dihydropyridine andtetrahydropyridine. Specific examples are pyrrole, imidazole, pyrazole,pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine andtetrazole.

The term as used herein “nitrogen-containing heterocyclyl” includes amonovalent group derived from the “nitrogen-containing heterocycle.”

The phrase as used herein “together with the carbon atom to which theyare attached may form a heterocycle” includes the “heterocycle” which isformed by two substituent and the carbon atom to which the substituentsare attached such as

wherein either one of bonds indicated by a and b bond to ring A,The phrase as used herein “together with the carbon atom to which theyare attached may form substituted or unsubstituted heterocycle” includesthe heterocycle optionally substituted with the substituents of theafter-mentioned “substituted or unsubstituted heterocycle.”

Examples of the substituent of “substituted or unsubstitutedcarbocycle”, “substituted or unsubstituted aromatic carbocycle”,“substituted or unsubstituted carbocyclyl”, “substituted orunsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkylsulfonylamino”, “substituted or unsubstituted cycloalkenyl”,“substituted or unsubstituted cycloalkenyl sulfonylamino”, “substitutedor unsubstituted aryl”, “substituted or unsubstitutedarylsulfonylamino”, “substituted or unsubstituted heterocycle”,“substituted or unsubstituted aromatic heterocycle”, “substituted orunsubstituted nitrogen containing heterocycle”, “substituted orunsubstituted heterocyclyl” and “substituted or unsubstitutedheterocyclylsulfonylamino” are one or more selected from the group oflower alkyl optionally substituted with one or more selected from theSubstituent Group α, lower alkenyl optionally substituted with one ormore selected from the Substituent Group α, lower alkynyl optionallysubstituted with one or more selected from the Substituent Group α,lower alkoxyl optionally substituted with one or more selected from theSubstituent Group α, and one or more selected from the Substituent Groupα.

The term “heteroaryl” as used herein includes aromatic heterocyclyl inthe “heterocyclyl.”

The phrase “a benzene ring fused with another ring” as used hereinincludes groups formed by fusion of a benzene ring and another cyclicgroup selected from the above “carbocycle” or the above “heterocycle”,and the examples are naphthalene, indane, indene, indole, isoindole,indazole, chromen, chroman, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, benzofuran, benzimidazole, benzisoxazole,benzopyrazole, benzothiophen, benzothiazole. Examples of “ring A is abenzene ring fused with another ring” includes

wherein R¹, R², R^(A), R^(B), R^(C), R^(D), m, n, and p are as definedabove, ring B is a carbocycle or a heterocycle.Examples of ring B are benzene, cycloalkane and pyridine.

The term “solvate” as used herein includes, for example, solvates withorganic solvents and hydrates. In the case that a hydrate is formed, thecompound or salt may be coordinated with any number of water molecules.

The compound of formula (I) include pharmaceutically acceptable saltsthereof. Examples thereof include salts with alkaline metals (e.g.lithium, sodium and potassium), alkaline earth metals (e.g. magnesiumand calcium), ammonium, organic bases and amino acids, and salts withinorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and hydroiodic acid) and organic acids(e.g. formic acid, acetic acid, trifluoroacetic acid, citric acid,lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid,mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid,benzenesulfonic acid, p-toluenesulfonic acid, methanosulfonic acid andethanesulfonic acid). Specifically preferable are hydrochloric acid,formic acid, hydroiodic acid and trifluoroacetic acid. These salts maybe formed by a routine method.

The compound of formula (I) is not limited to a specific isomer, andinclude any possible isomers (e.g. keto-enol isomers, imine-enamineisomers, diastereoisomers, optical isomers and rotamers) and racemicmixtures. For example, a compound (1) includes the following tautomers:

In addition, one or more hydrogen, carbon or other atoms of a compoundof formula (I) can be replaced by an isotope of the hydrogen, carbon orother atoms. Compounds of formula (I) include all radiolabeled forms ofcompounds of formula (I). The “radiolabeled,” “radiolabeled form”, andthe like of a compound of formula (I) are encompassed by the inventionand useful as a research and/or diagnostic tool in metabolismpharmacokinetic studies and in binding assays.

Examples of isotopes that can be incorporated into a compound of formula(I) of the invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Radiolabeled compounds of the invention can be prepared by methods knownin the art. For example, tritiated compounds of formula (I) can beprepared by introducing tritium into the particular compound of formula(I), for example, by catalytic dehalogenation with tritium. This methodmay include reacting a suitably halogen-substituted precursor of acompound of formula (I) with tritium gas in the presence of a suitablecatalyst such as Pd/C, in the presence or absence of a base. Othersuitable methods for preparing tritiated compounds can be found inFiler, “The Preparation and Characterization of TritiatedNeurochemicals,” Chapter 6, pp. 155.192 in Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A) (1987).¹⁴C-labeled compounds can be prepared by employing starting materialshaving a ¹⁴C carbon.

For example, the compound of formula (I) wherein X is a sulfur atom canbe prepared by the following procedures for synthesis of Compound d.

wherein each symbol is as defined above.

Step 1

To a solution of Compound a in a solvent such as dichloromethane,dioxane, tetrahydrofuran, toluene or acetone, or a mixed solvent thereofis added an isothiocyanate having a protecting group which iscommercially available such as benzoylisothiocyanate or which can beprepared by known methods. The mixture is allowed to treat at atemperature between −30° C. to 100° C., preferably between −20° C. to70° C. for 0.1 to 12 hours, preferably 0.1 to 4 hours to afford Compoundb.

Step 2

To a solution of Compound b in a solvent such as methanol, ethanol orisopropyl alcohol, or a mixed solvent thereof is added a base such as anaqueous solution of sodium hydroxide, an aqueous solution of potassiumhydroxide or an aqueous solution of lithium hydroxide. The mixture isallowed to treat at a temperature between −20° C. to 120° C., preferablybetween 10° C. to 100° C. for 0.1 to 6 hours, preferably 0.5 to 3 hoursto afforded Compound c.

Step 3

To a solution of Compound c in a solvent such as dioxane,tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetoamide,N-methyl pyrrolidone or acetone, or a mixed solvent thereof is added analkylating agent such as alkyl iodide, alkyl bromide or alkyl sulfate.The mixture is allowed to treat at a temperature between −20° C. to 120°C., preferably between 10° C. to 100° C. for 0.1 to 12 hours, preferably0.5 to 6 hours to afford Compound d.

Compound of the formula (I) can also be prepared from Compound b by thefollowing procedures for synthesis of Compound d

wherein each symbol is as defined above.

Step 1

To a solution of Compound b in a solvent such as methanol, ethanol orisopropyl alcohol, or a mixed solvent thereof is added a base such as anaqueous solution of sodium hydroxide, an aqueous solution of potassiumhydroxide or an aqueous solution of lithium hydroxide. The mixture isallowed to treat at a temperature between −20° C. to 120° C., preferablybetween 10° C. to 100° C. for 0.1 to 6 hours, preferably 0.5 to 3 hours.

Then the mixture is extracted and the extract is dissolved in a solventsuch as dioxane, tetrahydrofuran, acetonitrile, dimethylformamide,dimethylacetoamide, N-methylpyrrolidone or acetone, or a mixed solventthereof. An alkylating agent such as alkyl iodide, alkyl bromide oralkyl sulfate is added to the mixture and the mixture is allowed totreat at a temperature between −20° C. to 120° C., preferably between10° C. to 100° C. for 0.1 to 12 bolus, preferably 0.5 to 6 hours.

The mixture is concentrated and replaced a solvent such as methanol,ethanol, isopropylalcohol, dimethylformamide or tetrahydrofuran, or amixed solvent thereof. A base such as triethylamine, diisopropylamine,diisopropylethyl and a Boc agent such as t-butyl dicarbonate are addedto the mixture and the mixture is allowed to treat at a temperaturebetween −20° C. to 120° C., preferably between 10° C. to 100° C. or 0.1to 4 hours, preferably, 0.5 to 2 hours to afford Compound e.

Step 2

To a solution of Compound e in a solvent such as dichloromethan,chloroform, dioxane, tetrahydrofuran, acetonitrile or acetone, or amixed solvent thereof is added an acid such as trifluoroacetic acid,hydrochloric acid or hydrobromic acid. The mixture is allowed to treatat a temperature between −20° C. to 100° C., preferably between 10° C.to 80° C. for 0.1 to 4 hours, preferably 0.5 to 2 hours to affordCompound U.

For example, the compound of formula (I) wherein X is an oxygen atom canbe prepared by the following procedures for synthesis of Compound g.

wherein each symbol is as defined above.

Step 1

To a solution of Compound a in a solvent such as dichloromethane,chloroform, dioxane, tetrahydrofuran, toluene, acetone or methanol, or amixed solvent thereof are added cyanogen bromide and, if necessary, abase such as triethylamine, sodium carbonate or sodium hydrogencarbonate. The mixture is allowed to treat at a temperature between −30°C. to 100° C., preferably between −10° C. to 80° C. for 0.1 to 6 hours,preferably 0.5 to 4 hours to afford Compound f.

Step 2

To a solution of Compound f in lower alkyl alcohol such as methanol isadded an acid such as hydrogen chloride, sulfuric acid or perchloricacid. The mixture is allowed to treat at a temperature between −30° C.to 100° C., preferably between −10° C. to 50° C. for 0.5 to 6 hours,preferably 1 to 4 hours to afford Compound g.

In the case that a substituent which inhibits a reaction (e.g. hydroxy,mercapto, amino, formyl, carbonyl and carboxy) exists in any of theabove steps, the substituent may be preliminarily protected by, forexample, the method described in “Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons)”, and the protectinggroup may be removed at a desired step.

Further, during all the above-mentioned steps, the order of the steps tobe performed may be appropriately changed. In each step, an intermediatemay be isolated and then used in the next step.

The following embodiments are exemplified for the compound of thepresent invention.

The compound of formula (I):

wherein X is an oxygen atom or sulfur atom, m is an integer of 0, and1) ring A is benzene (hereinafter referred to as “ring A is A1”), ring Ais a benzene ring fused with another ring (hereinafter referred to as“ring A is A2”), orring A is naphthalene, indane, quinoline or chromane (hereinafterreferred to as “ring A is A3”),2) R¹ is substituted or unsubstituted acylamino (hereinafter referred toas “R¹ is R11”), R¹ is substituted or unsubstituted acylamino whereinthe substituent is one or more selected from the group of halogen,hydroxy, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy,lower alkenyloxy and lower alkynyloxy (hereinafter referred to as “R¹ isR12”),R¹ is substituted or unsubstituted acyl amino wherein acyl iscarbocyclylcarbonyl or heterocyclylcarbonyl and the substituent is oneor more selected from the group of halogen, hydroxy, cyano, lower alkyl,lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, loweralkynyl oxy, carboxy, lower alkoxycarbonyl, amino, alkylamino,acylamino, imino, mercapto, lower alkylthio, lower alkenylthio, loweralkynylthio, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, loweralkylsulfonyl, lower alkenylsulfamoyl, lower alkenylsulfinyl, loweralkenylsulfonyl, lower alkynylsulfamoyl, lower alkynylsulfinyl, loweralkynylsulfonyl, acyl, nitro, oxo, carbocyclyl optionally substitutedwith one or more selected from Substituent Group γ and heterocyclyloptionally substituted with one or more selected from Substituent Groupγ (hereinafter referred to as “R¹ is R13”),R¹ is substituted or unsubstituted acylamino wherein acyl iscarbocyclylcarbonyl or heterocyclylcarbonyl and the substituent is oneor more selected from the group of halogen, hydroxy, cyano, lower alkyl,lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy and loweralkynyoxy (hereinafter referred to as “R¹ is R14”),R¹ is substituted or unsubstituted halogenosulfonylamino, substituted orunsubstituted lower alkylsulfonylamino, substituted or unsubstitutedlower alkenylsulfonyl amino, substituted or unsubstituted loweralkynylsulfonylamino, substituted or unsubstitutedcycloalkylsulfonylamino, substituted or unsubstitutedcycloalkenylsulfonylamino, substituted or unsubstitutedacylsulfonylamino, substituted or unsubstituted arylsulfonylamino orsubstituted or unsubstituted heterocyclylsulfonylamino (hereinafterreferred to as “R¹ is R15”),R¹ is unsubstituted lower alkylsulfonylamino (hereinafter referred to as“R¹ is R16”),R¹ is substituted or unsubstituted aryl (hereinafter referred to as “R¹is R17”),R¹ is aryl wherein the substituent is one or more selected from thegroup of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl,lower alkoxy, lower alkenyloxy, lower alkynyloxy, amino, acylamino,lower alkoxy acylamino, lower alkenyloxy acylamino and lower alkynyloxyacylamino (hereinafter referred to as “R¹ is R18”), orR¹ is substituted or unsubstituted heterocyclyl whrein the substituentis one or more selected from the group of halogen, hydroxy, lower alkyl,lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, loweralkynyloxy, amino, acylamino, lower alkoxy acylamino, lower alkenyloxyacylamino and lower alkynyloxy acylamino (hereinafter referred to as “R¹is R19”),3) n is an integer of 0 (hereinafter referred to as “R² is R21”),n is an integer of 1, and R² is halogen (hereinafter referred to as “R²is R22”),n is an integer of 1, and R² is substituted or unsubstituted lower alkyl(hereinafter referred to as “R² is R23”),n is an integer of 1, and R² is unsubstituted lower alkyl (hereinafterreferred to as “R² is R24”),n is an integer of 1, and R² is substituted or unsubstituted aminowherein the substituent is one or more selected from the group of loweralkyl, lower alkenyl, lower alkynyl, acyl, lower alkoxycarbonyl,halogenosulfonyl, lower alkylsulfonyl, lower alkenylsulfonyl, loweralkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, acylsulfonyl,arylsulfonyl, heterocyclylsulfonyl, carbocyclyl optionally substitutedwith one or more selected from Substituent Group γ and heterocyclyloptionally substituted with one or more selected from Substituent Groupγ (hereinafter referred to as “R² is R25”), orn is an integer of 1, and R² is substituted or unsubstituted hydroxywherein the substituent is one or more selected from the group of loweralkyl, lower alkenyl, lower alkynyl, acyl, lower alkoxycarbonyl,halogenosulfonyl, lower alkylsulfonyl, lower alkenylsulfonyl, loweralkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, acylsulfonyl,arylsulfonyl, heterocyclylsulfonyl, aryl lower alkyl optionallysubstituted with one or more selected from Substituent Group γ,carbocyclyl optionally substituted with one or more selected fromSubstituent Group γ and heterocyclyl optionally substituted with one ormore selected from Substituent Group γ (hereinafter referred to as “R²is R26”),4) R³ is substituted or unsubstituted lower alkyl (hereinafter referredto as “R³ is R31”), R³ is substituted or unsubstituted lower alkylwherein the substituent is one or more selected from the group ofhalogen, hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy,amino, lower alkylamino, lower alkenylamino, lower alkynylamino,acylamino, carbocyclyl and heterocyclyl (hereinafter referred to as “R³is R32”),R³ is unsubstituted lower alkyl (hereinafter referred to as “R³ isR33”),R³ is substituted or unsubstituted lower alkenyl (hereinafter referredto as “R³ is R34”), orR³ is unsubstituted lower alkenyl wherein the substituent is one or moreselected from the group of halogen, hydroxy, lower alkoxy, loweralkenyloxy, lower alkynyloxy, amino, lower alkylamino, loweralkenylamino, lower alkynylamino, acylamino, carbocyclyl andheterocyclyl (hereinafter referred to as “R³ is R35”), or5) p is an integer of 0 (hereinafter referred to as “R^(C) and R^(D) areCD1”),p is an intger of 1 or 2, and R^(C) and R^(D) are all hydrogen(hereinafter referred to as “R^(C) and R^(D) are CD2”),p is an integer of 1 or 2, and R^(C) and R^(D) are each independentlyhydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl or substituted or unsubstituted heterocyclyl(hereinafter referred to as “R^(C) and R^(D) are CD3”), R^(C) and R^(D)are each independently hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted aryl or substituted or unsubstitutedheterocyclyl wherein the substituent is one or more selected from thegroup of halogen, hydroxy, lower alkoxy, lower alkenyloxy, loweralkynyloxy, lower alkoxycarbonyl, carbocyclyl lower alkoxy orheterocyclyl lower alkoxy (hereinafter referred to as “R^(C) and R^(D)are CD4”),p is an integer of 1 or 2, and R^(C) and R^(D) are each independentlyhydrogen, unsubstituted lower alkyl, halogenolower alkyl, substituted orunsubstituted phenyl or substituted or unsubstituted nitrogen-containingheterocyclyl wherein the substituent is one or more selected from thegroup of halogen, lower alkoxy, lower alkoxycarbonyl and aryl loweralkoxy (hereinafter referred to as “R^(C) and R^(D) are CD5),p is an integer of 1, and R^(C) and R^(D) together with the carbon atomto which they are attached may form a substituted or unsubstitutedcarbocycle (hereinafter referred to as “R^(C) and R^(D) are CD6”), orp is an integer of 1, and R^(C) and R^(D) together with the carbon atomto which they are attached may form an unsubstituted cycloalkane ring(hereinafter referred to as “R^(C) and R^(D) are CD7”).

A compound of formula (I) wherein X is an oxygen atom or a sulfur atom,

m is an integer of 0, and the combination of ring A, R¹, n and R², R³,R^(C) and R^(D), and p is as follows:

(A1, R11, R21, R31, CD1), (A1, R11, R21, R31, CD2), (A1, R11, R21, R31,CD3), (A1, R11, R21, R31, CD4), (A1, R11, R21, R31, CD5), (A1, R11, R21,R31, CD6), (A1, R11, R21, R31, CD7), (A1, R11, R21, R32, CD1), (A1, R11,R21, R32, CD2), (A1, R11, R21, R32, CD3), (A1, R11, R21, R32, CD4), (A1,R11, R21, R32, CD5), (A1, R11, R21, R32, CD6), (A1, R11, R21, R32, CD7),(A1, R11, R21, R33, CD1), (A1, R11, R21, R33, CD2), (A1, R11, R21, R33,CD3), (A1, R11, R21, R33, CD4), (A1, R11, R21, R33, CD5), (A1, R11, R21,R33, CD6), (A1, R11, R21, R33, CD7), (A1, R11, R21, R34, CD1), (A1, R11,R21, R34, CD2), (A1, R11, R21, R34, CD3), (A1, R11, R21, R34, CD4), (A1,R11, R21, R34, CD5), (A1, R11, R21, R34, CD6), (A1, R11, R21, R34, CD7),(A1, R11, R21, R35, CD1), (A1, R11, R21, R35, CD2), (A1, R11, R21, R35,CD3), (A1, R11, R21, R35, CD4), (A1, R11, R21, R35, CD5), (A1, R11, R21,R35, CD6), (A1, R11, R21, R35, CD7), (A1, R11, R22, R31, CD1), (A1, R11,R22, R31, CD2), (A1, R11, R22, R31, CD3), (A1, R11, R22, R31, CD4), (A1,R11, R22, R31, CD5), (A1, R11, R22, R31, CD6), (A1, R11, R22, R31, CD7),(A1, R11, R22, R32, CD1), (A1, R11, R22, R32, CD2), (A1, R11, R22, R32,CD3), (A1, R11, R22, R32, CD4), (A1, R11, R22, R32, CD5), (A1, R11, R22,R32, CD6), (A1, R11, R22, R32, CD7), (A1, R11, R22, R33, CD1), (A1, R11,R22, R33, CD2), (A1, R11, R22, R33, CD3), (A1, R11, R22, R33, CD4), (A1,R11, R22, R33, CD5), (A1, R11, R22, R33, CD6), (A1, R11, R22, R33, CD7),(A1, R11, R22, R34, CD1), (A1, R11, R22, R34, CD2), (A1, R11, R22, R34,CD3), (A1, R11, R22, R34, CD4), (A1, R11, R22, R34, CD5), (A1, R11, R22,R34, CD6), (A1, R11, R22, R34, CD7), (A1, R11, R22, R35, CD1), (A1, R11,R22, R35, CD2), (A1, R11, R22, R35, CD3), (A1, R11, R22, R35, CD4), (A1,R11, R22, R35, CD5), (A1, R11, R22, R35, CD6), (A1, R11, R22, R35, CD7),(A1, R11, R23, R31, CD1), (A1, R11, R23, R31, CD2), (A1, R11, R23, R31,CD3), (A1, R11, R23, R31, CD4), (A1, R11, R23, R31, CD5), (A1, R11, R23,R31, CD6), (A1, R11, R23, R31, CD7), (A1, R11, R23, R32, CD1), (A1, R11,R23, R32, CD2), (A1, R11, R23, R32, CD3), (A1, R11, R23, R32, CD4), (A1,R11, R23, R32, CD5), (A1, R11, R23, R32, CD6), (A1, R11, R23, R32, CD7),(A1, R11, R23, R33, CD1), (A1, R11, R23, R33, CD2), (A1, R11, R23, R33,CD3), (A1, R11, R23, R33, CD4), (A1, R11, R23, R33, CD5), (A1, R11, R23,R33, CD6), (A1, R11, R23, R33, CD7), (A1, R11, R23, R34, CD1), (A1, R11,R23, R34, CD2), (A1, R11, R23, R34, CD3), (A1, R11, R23, R34, CD4), (A1,R11, R23, R34, CD5), (A1, R11, R23, R34, CD6), (A1, R11, R23, R34, CD7),(A1, R11, R23, R35, CD1), (A1, R11, R23, R35, CD2), (A1, R11, R23, R35,CD3), (A1, R11, R23, R35, CD4), (A1, R11, R23, R35, CD5), (A1, R11, R23,R35, CD6), (A1, R11, R23, R35, CD7), (A1, R11, R24, R31, CD1), (A1, R11,R24, R31, CD2), (A1, R11, R24, R31, CD3), (A1, R11, R24, R31, CD4), (A1,R11, R24, R31, CD5), (A1, R11, R24, R31, CD6), (A1, R11, R24, R31, CD7),(A1, R11, R24, R32, CD1), (A1, R11, R24, R32, CD2), (A1, R11, R24, R32,CD3), (A1, R11, R24, R32, CD4), (A1, R11, R24, R32, CD5), (A1, R11, R24,R32, CD6), (A1, R11, R24, R32, CD7), (A1, R11, R24, R33, CD1), (A1, R11,R24, R33, CD2), (A1, R11, R24, R33, CD3), (A1, R11, R24, R33, CD4), (A1,R11, R24, R33, CD5), (A1, R11, R24, R33, CD6), (A1, R11, R24, R33, CD7),(A1, R11, R24, R34, CD1), (A1, R11, R24, R34, CD2), (A1, R11, R24, R34,CD3), (A1, R11, R24, R34, CD4), (A1, R11, R24, R34, CD5), (A1, R11, R24,R34, CD6), (A1, R11, R24, R34, CD7), (A1, R11, R24, R35, CD1), (A1, R11,R24, R35, CD2), (A1, R11, R24, R35, CD3), (A1, R11, R24, R35, CD4), (A1,R11, R24, R35, CD5), (A1, R11, R24, R35, CD6), (A1, R11, R24, R35, CD7),(A1, R11, R25, R31, CD1), (A1, R11, R25, R31, CD2), (A1, R11, R25, R31,CD3), (A1, R11, R25, R31, CD4), (A1, R11, R25, R31, CD5), (A1, R11, R25,R31, CD6), (A1, R11, R25, R31, CD7), (A1, R11, R25, R32, CD1), (A1, R11,R25, R32, CD2), (A1, R11, R25, R32, CD3), (A1, R11, R25, R32, CD4), (A1,R11, R25, R32, CD5), (A1, R11, R25, R32, CD6), (A1, R11, R25, R32, CD7),(A1, R11, R25, R33, CD1), (A1, R11, R25, R33, CD2), (A1, R11, R25, R33,CD3), (A1, R11, R25, R33, CD4), (A1, R11, R25, R33, CD5), (A1, R11, R25,R33, CD6), A1, R11, R25, R33, CD7), A1, R11, R25, R34, CD1), A1, R11,R25, R34, CD2), A1, R11, R25, R34, CD3), (A1, R11, R25, R34, CD4), (A1,R11, R25, R34, CD5), (A1, R11, R25, R34, CD6), (A1, R11, R25, R34, CD7),(A1, R11, R25, R35, CD1), (A1, R11, R25, R35, CD2), (A1, R11, R25, R35,CD3), (A1, R11, R25, R35, CD4), (A1, R11, R25, R35, CD5), (A1, R11, R25,R35, CD6), (A1, R11, R25, R35, CD7), (A1, R11, R26, R31, CD1), (A1, R11,R26, R31, CD2), (A1, R11, R26, R31, CD3), (A1, R11, R26, R31, CD4), (A1,R11, R26, R31, CD5), (A1, R11, R26, R31, CD6), (A1, R11, R26, R31, CD7),(A1, R11, R26, R32, CD1), (A1, R11, R26, R32, CD2), (A1, R11, R26, R32,CD3), (A1, R11, R26, R32, CD4), (A1, R11, R26, R32, CD5), (A1, R11, R26,R32, CD6), (A1, R11, R26, R32, CD7), (A1, R11, R26, R33, CD1), (A1, R11,R26, R33, CD2), (A1, R11, R26, R33, CD3), (A1, R11, R26, R33, CD4), (A1,R11, R26, R33, CD5), (A1, R11, R26, R33, CD6), (A1, R11, R26, R33, CD7),(A1, R11, R26, R34, CD1), (A1, R11, R26, R34, CD2), (A1, R11, R26, R34,CD3), (A1, R11, R26, R34, CD4), (A1, R11, R26, R34, CD5), (A1, R11, R26,R34, CD6), (A1, R11, R26, R34, CD7), (A1, R11, R26, R35, CD1), (A1, R11,R26, R35, CD2), (A1, R11, R26, R35, CD3), (A1, R11, R26, R35, CD4), (A1,R11, R26, R35, CD5), (A1, R11, R26, R35, CD6), (A1, R11, R26, R35, CD7),(A1, R12, R21, R31, CD1), (A1, R12, R21, R31, CD2), (A1, R12, R21, R31,CD3), (A1, R12, R21, R31, CD4), A1, R12, R21, R31, CD5), (A1, R12, R21,R31, CD6), (A1, R12, R21, R31, CD7), (A1, R12, R21, R32, CD1), (A1, R12,R21, R32, CD2), (A1, R12, R21, R32, CD3), (A1, R12, R21, R32, CD4), (A1,R12, R21, R32, CD5), (A1, R12, R21, R32, CD6), (A1, R12, R21, R32, CD7),(A1, R12, R21, R33, CD1), (A1, R12, R21, R33, CD2), (A1, R12, R21, R33,CD3), (A1, R12, R21, R33, CD4), (A1, R12, R21, R33, CD5), (A1, R12, R21,R33, CD6), (A1, R12, R21, R33, CD7), (A1, R12, R21, R34, CD1), (A1, R12,R21, R34, CD2), (A1, R12, R21, R34, CD3), (A1, R12, R21, R34, CD4), (A1,R12, R21, R34, CD5), (A1, R12, R21, R34, CD6), (A1, R12, R21, R34, CD7),(A1, R12, R21, R35, CD1), (A1, R12, R21, R35, CD2), (A1, R12, R21, R35,CD3), (A1, R12, R21, R35, CD4), (A1, R12, R21, R35, CD5), (A1, R12, R21,R35, CD6), (A1, R12, R21, R35, CD7), (A1, R12, R22, R31, CD1), (A1, R12,R22, R31, CD2), (A1, R12, R22, R31, CD3), (A1, R12, R22, R31, CD4), (A1,R12, R22, R31, CD5), (A1, R12, R22, R31, CD6), (A1, R12, R22, R31, CD7),(A1, R12, R22, R32, CD1), (A1, R12, R22, R32, CD2), (A1, R12, R22, R32,CD3), (A1, R12, R22, R32, CD4), (A1, R12, R22, R32, CD5), (A1, R12, R22,R32, CD6), (A1, R12, R22, R32, CD7), A1, R12, R22, R33, CD1), (A1, R12,R22, R33, CD2), (A1, R12, R22, R33, CD3), (A1, R12, R22, R33, CD4), (A1,R12, R22, R33, CD5), (A1, R12, R22, R33, CD6), (A1, R12, R22, R33, CD7),(A1, R12, R22, R34, CD1), (A1, R12, R22, R34, CD2), A1, R12, R22, R34,CD3), (A1, R12, R22, R34, CD4), (A1, R12, R22, R34, CD5), (A1, R12, R22,R34, CD6), (A1, R12, R22, R34, CD7), (A1, R12, R22, R35, CD1), (A1, R12,R22, R35, CD2), (A1, R12, R22, R35, CD3), (A1, R12, R22, R35, CD4), (A1,R12, R22, R35, CD5), (A1, R12, R22, R35, CD6), (A1, R12, R22, R35, CD7),(A1, R12, R23, R31, CD1), (A1, R12, R23, R31, CD2), (A1, R12, R23, R31,CD3), (A1, R12, R23, R31, CD4), (A1, R12, R23, R31, CD5), (A1, R12, R23,R31, CD6), (A1, R12, R23, R31, CD7), (A1, R12, R23, R32, CD1), (A1, R12,R23, R32, CD2), (A1, R12, R23, R32, CD3), (A1, R12, R23, R32, CD4), (A1,R12, R23, R32, CD5), (A1, R12, R23, R32, CD6), (A1, R12, R23, R32, CD7),(A1, R2, R23, R33, CD1), (A1, R12, R23, R33, CD2), (A1, R12, R23, R33,CD3), 1, R12, R23, R33, CD4), (A1, R12, R23, R33, CD5), (A1, R12, R23,R33, CD6), (A1, R12, R23, R33, CD7), (A1, R12, R23, R34, CD1), (A1, R12,R23, R34, CD2), (A1, R12, R23, R34, CD3), (A1, R12, R23, R34, CD4), (A1,R12, R23, R34, CD5), (A1, R12, R23, R34, CD6), (A1, R12, R23, R34, CD7),A1, R12, R23, R35, CD1), (A1, R12, R23, R35, CD2), (A1, R12, R23, R35,CD3), (A1, R12, R23, R35, CD4), (A1, R12, R23, R35, CD5), (A1, R12, R23,R35, CD6), (A1, R12, R23, R35, CD7), (A1, R12, R24, R31, CD1), (A1, R12,R24, R31, CD2), A1, R12, R24, R31, CD3), A1, R12, R24, R31, CD4), A1,R12, R24, R31, CD5), (A1, R12, R24, R31, CD6), (A1, R12, R24, R31, CD7),(A1, R12, R24, R32, CD1), (A1, R12, R24, R32, CD2), (A1, R12, R24, R32,CD3), (A1, R12, R24, R32, CD4), (A1, R12, R24, R32, CD5), (A1, R12, R24,R32, CD6), (A1, R12, R24, R32, CD7), (A1, R12, R24, R33, CD1), (A1, R12,R24, R33, CD2), (A1, R12, R24, R33, CD3), (A1, R12, R24, R33, CD4), (A1,R12, R24, R33, CD5), (A1, R12, R24, R33, CD6), (A1, R12, R24, R33, CD7),(A1, R12, R24, R34, CD1), (A1, R12, R24, R34, CD2), (A1, R12, R24, R34,CD3), (A1, R12, R24, R34, CD4), (A1, R12, R24, R34, CD5), (A1, R12, R24,R34, CD6), (A1, R12, R24, R34, CD7), (A1, R12, R24, R35, CD1), (A1, R12,R24, R35, CD2), (A1, R12, R24, R35, CD3), (A1, R12, R24, R35, CD4), (A1,R12, R24, R35, CD5), (A1, R12, R24, R35, CD6), (A1, R12, R24, R35, CD7),(A1, R12, R25, R31, CD1), A1, R12, R25, R31, CD2), A1, R12, R25, R31,CD3), A1, R12, R25, R31, CD4), (A1, R12, R25, R31, CD5), (A1, R12, R25,R31, CD6), (A1, R12, R25, R31, CD7), (A1, R12, R25, R32, CD1), A1, R12,R25, R32, CD2), A1, R12, R25, R32, CD3), A1, R12, R25, R32, CD4), (A1,R12, R25, R32, CD5), (A1, R12, R25, R32, CD6), (A1, R12, R25, R32, CD7),(A1, R12, R25, R33, CD1), (A1, R12, R25, R33, CD2), (A1, R12, R25, R33,CD3), (A1, R12, R25, R33, CD4), (A1, R12, R25, R33, CD5), (A1, R12, R25,R33, CD6), (A1, R12, R25, R33, CD7), (A1, R12, R25, R34, CD1), (A1, R12,R25, R34, CD2), (A1, R12, R25, R34, CD3), (A1, R12, R25, R34, CD4), (A1,R12, R25, R34, CD5), (A1, R12, R25, R34, CD6), (A1, R12, R25, R34, CD7),(A1, R12, R25, R35, CD1), (A1, R12, R25, R35, CD2), (A1, R12, R25, R35,CD3), (A1, R12, R25, R35, CD4), (A1, R12, R25, R35, CD5), (A1, R12, R25,R35, CD6), (A1, R12, R25, R35, CD7), (A1, R12, R26, R31, CD1), (A1, R12,R26, R31, CD2), (A1, R12, R26, R31, CD3), (A1, R12, R26, R31, CD4), (A1,R12, R26, R31, CD5), (A1, R12, R26, R31, CD6), (A1, R12, R26, R31, CD7),(A1, R12, R26, R32, CD1), (A1, R12, R26, R32, CD2), (A1, R12, R26, R32,CD3), (A1, R12, R26, R32, CD4), (A1, R12, R26, R32, CD5), (A1, R12, R26,R32, CD6), (A1, R12, R26, R32, CD7), (A1, R12, R26, R33, CD1), (A1, R12,R26, R33, CD2), (A1, R12, R26, R33, CD3), (A1, R12, R26, R33, CD4), (A1,R12, R26, R33, CD5), (A1, R12, R26, R33, CD6), (A1, R12, R26, R33, CD7),(A1, R12, R26, R34, CD1), (A1, R12, R26, R34, CD2), (A1, R12, R26, R34,CD3), (A1, R12, R26, R34, CD4), (A1, R12, R26, R34, CD5), (A1, R12, R26,R34, CD6), (A1, R12, R26, R34, CD7), (A1, R12, R26, R35, CD1), (A1, R12,R26, R35, CD2), (A1, R12, R26, R35, CD3), (A1, R12, R26, R35, CD4), (A1,R12, R26, R35, CD5), (A1, R12, R26, R35, CD6), (A1, R12, R26, R35, CD7),(A1, R13, R21, R31, CD1), (A1, R13, R21, R31, CD2), (A1, R13, R21, R31,CD3), (A1, R13, R21, R31, CD4), (A1, R13, R21, R31, CD5), (A1, R13, R21,R31, CD6), (A1, R13, R21, R31, CD7), (A1, R13, R21, R32, CD1), (A1, R13,R21, R32, CD2), (A1, R13, R21, R32, CD3), (A1, R13, R21, R32, CD4), (A1,R13, R21, R32, CD5), (A1, R13, R21, R32, CD6), (A1, R13, R21, R32, CD7),(A1, R13, R21, R33, CD1), (A1, R13, R21, R33, CD2), (A1, R13, R21, R33,CD3), (A1, R13, R21, R33, CD4), (A1, R13, R21, R33, CD5), (A1, R13, R21,R33, CD6), A1, R13, R21, R33, CD7), (A1, R13, R21, R34, CD1), (A1, R13,R21, R34, CD2), (A1, R13, R21, R34, CD3), (A1, R13, R21, R34, CD4), (A1,R13, R21, R34, CD5), (A1, R13, R21, R34, CD6), (A1, R13, R21, R34, CD7),(A1, R13, R21, R35, CD1), (A1, R13, R21, R36, CD2), (A1, R13, R21, R35,CD3), (A1, R13, R21, R35, CD4), (A1, R13, R21, R35, CD5), (A1, R13, R21,R35, CD6), (A1, R13, R21, R35, CD7), (A1, R13, R22, R31, CD1), (A1, R13,R22, R31, CD2), (A1, R13, R22, R31, CD3), (A1, R13, R22, R31, CD4), (A1,R13, R22, R31, CD5), (A1, R13, R22, R31, CD6), (A1, R13, R22, R31, CD7),(A1, R13, R22, R32, CD1), (A1, R13, R22, R32, CD2), (A1, R13, R22, R32,CD3), (A1, R13, R22, R32, CD4), (A1, R13, R22, R32, CD5), (A1, R13, R22,R32, CD6), (A1, R13, R22, R32, CD7), (A1, R13, R22, R33, CD1), (A1, R13,R22, R33, CD2), (A1, R13, R22, R33, CD3), (A1, R13, R22, R33, CD4), (A1,R13, R22, R33, CD5), (A1, R13, R22, R33, CD6), (A1, R13, R22, R33, CD7),(A1, R13, R22, R34, CD1), (A1, R13, R22, R34, CD2), (A1, R13, R22, R34,CD3), (A1, R13, R22, R34, CD4), (A1, R13, R22, R34, CD5), (A1, R13, R22,R34, CD6), (A1, R13, R22, R34, CD7), (A1, R13, R22, R35, CD1), (A1, R13,R22, R35, CD2), (A1, R13, R22, R35, CD3), (A1, R13, R22, R35, CD4), (A1,R13, R22, R35, CD5), (A1, R13, R22, R35, CD6), (A1, R13, R22, R35, CD7),(A1, R13, R23, R31, CD1), (A1, R13, R23, R31, CD2), (A1, R13, R23, R31,CD3), (A1, R13, R23, R31, CD4), (A1, R13, R23, R31, CD5), (A1, R13, R23,R31, CD6), (A1, R13, R23, R31, CD7), (A1, R13, R23, R32, CD1), (A1, R13,R23, R32, CD2), (A1, R13, R23, R32, CD3), (A1, R13, R23, R32, CD4), (A1,R13, R23, R32, CD5), (A1, R13, R23, R32, CD6), (A1, R13, R23, R32, CD7),(A1, R13, R23, R33, CD1), (A1, R13, R23, R33, CD2), (A1, R13, R23, R33,CD3), (A1, R13, R23, R33, 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(A1, R18, R23, R34, CD1), A1, R18,R23, R34, CD2), (A1, R18, R23, R34, CD3), (A1, R18, R23, R34, CD4), A1,R18, R23, R34, CD5), (A1, R18, R23, R34, CD6), (A1, R18, R23, R34, CD7),(A1, R18, R23, R35, CD1), 1, R18, R23, R35, CD2), (A1, R18, R23, R35,CD3), (A1, R18, R23, R35, CD4), (A1, R18, R23, R35, CD5), (A1, R18, R23,R35, CD6), (A1, R18, R23, R35, CD7), (A1, R18, R24, R31, CD1), (A1, R18,R24, R31, CD2), (A1, R18, R24, R31, CD3), (A1, R18, R24, R31, CD4), (A1,R18, R24, R31, CD5), (A1, R18, R24, R31, CD6), (A1, R18, R24, R31, CD7),(A1, R18, R24, R32, CD1), (A1, R18, R24, R32, CD2), (A1, R18, R24, R32,CD3), (A1, R18, R24, R32, CD4), A1, R18, R24, R32, CD5), (A1, R18, R24,R32, CD6), (A1, R18, R24, R32, CD7), (A1, R18, R24, R33, CD1), (A1, R18,R24, R33, CD2), (A1, R18, R24, R33, CD3), (A1, R18, R24, R33, CD4), (A1,R18, R24, R33, CD5), (A1, R18, R24, R33, CD6), (A1, R18, R24, R33, CD7),(A1, R18, R24, R34, CD1), (A1, R18, R24, R34, CD2), (A1, R18, R24, R34,CD3), (A1, R18, R24, R34, CD4), (A1, R18, R24, R34, CD5), (A1, R18, R24,R34, CD6), (A1, R18, R24, R34, CD7), (A1, R18, R24, R35, CD1), (A1, R18,R24, R35, CD2), (A1, R18, R24, R35, CD3), (A1, R18, R24, R35, CD4), (A1,R18, R24, R35, CD5), (A1, R18, R24, R35, CD6), (A1, R18, R24, R35, CD7),(A1, R18, R25, R31, CD1), (A1, R18, R25, R31, CD2), (A1, R18, R25, R31,CD3), (A1, R18, R25, R31, CD4), (A1, R18, R25, R31, CD5), (A1, R18, R25,R31, CD6), (A1, R18, R25, R31, CD7), (A1, R18, R25, R32, CD1), (A1, R18,R25, R32, CD2), (A1, R18, R25, R32, CD 3), (A1, R18, R25, R32, CD4),(A1, R18, R25, R32, CD5), (A1, R18, R25, R32, CD6), (A1, R18, R25, R32,CD7), (A1, R18, R25, R33, CD1), (A1, R18, R25, R33, CD2), (A1, R18, R25,R33, CD3), (A1, R18, R25, R33, CD4), (A1, R18, R25, R33, CD5), (A1, R18,R25, R33, CD6), (A1, R18, R25, R33, CD7), (A1, R18, R25, R34, CD1), (A1,R18, R25, R34, CD2), (A1, R18, R25, R34, CD3), (A1, R18, R25, R34, CD4),(A1, R18, R25, R34, CD5), (A1, R18, R25, R34, CD6), (A1, R18, R25, R34,CD7), (A1, R18, R25, R35, CD1), (A1, R18, R25, R35, CD2), (A1, R18, R25,R35, CD3), A1, R18, R25, R35, CD4), (A1, R18, R25, R35, CD5), (A1, R18,R25, R35, CD6), (A1, R18, R25, R35, CD7), (A1, R18, R26, R31, CD1), (A1,R18, R26, R31, CD2), (A1, R18, R26, R31, CD3), (A1, R18, R26, R31, CD4),(A1, R18, R26, R31, CD5), (A1, R18, R26, R31, CD6), (A1, R18, R26, R31,CD7), (A1, R18, R26, R32, CD1), (A1, R18, R26, R32, CD2), (A1, R18, R26,R32, CD3), (A1, R18, R26, R32, CD4), (A1, R18, R26, R32, CD5), (A1, R18,R26, R32, CD6), (A1, R18, R26, R32, CD7), (A1, R18, R26, R33, CD1), A1,R18, R26, R33, CD2), (A1, R18, R26, R33, CD3), (A1, R18, R26, R33, CD4),(A1, R18, R26, R33, CD5), (A1, R18, R26, R33, CD6), (A1, R18, R26, R33,CD7), (A1, R18, R26, R34, CD1), (A1, R18, R26, R34, CD2), (A1, R18, R26,R34, CD3), (A1, R18, R26, R34, CD4), (A1, R18, R26, R34, CD5), (A1, R18,R26, R34, CD6), (A1, R18, R26, R34, CD7), (A1, R18, R26, R35, CD1), (A1,R18, R26, R35, CD2), (A1, R18, R26, R35, CD3), (A1, R18, R26, R35, CD4),(A1, R18, R26, R35, CD5), (A1, R18, R26, R35, CD6), (A1, R18, R26, R35,CD7), (A1, R19, R21, R31, CD1), (A1, R19, R21, R31, CD2), (A1, R19, R21,R31, CD3), (A1, R19, R21, R31, CD4), (A1, R19, R21, R31, CD5), (A1, R19,R21, R31, CD6), (A1, R19, R21, R31, CD7), (A1, R19, R21, R32, CD1), (A1,R19, R21, R32, CD2), (A1, R19, R21, R32, CD3), (A1, R19, R21, R32, CD4),(A1, R19, R21, R32, CD5), (A1, R19, R21, R32, CD6), (A1, R19, R21, R32,CD7), (A1, R19, R21, R33, CD1), (A1, R19, R21, R33, CD2), (A1, R19, R21,R33, CD3), (A1, R19, R21, R33, CD4), (A1, R19, R21, R33, CD5), (A1, R19,R21, R33, CD6), (A1, R19, R21, R33, CD7), (A1, R19, R21, R34, CD1), (A1,R19, R21, R34, CD2), (A1, R19, R21, R34, CD3), (A1, R19, R21, R34, CD4),(A1, R19, R21, R34, CD5), (A1, R19, R21, R34, CD6), (A1, R19, R21, R34,CD7), (A1, R19, R21, R35, CD1), (A1, R19, R21, R35, CD2), (A1, R19, R21,R35, CD3), (A1, R19, R21, R35, CD4), (A1, R19, R21, R35, CD5), (A1, R19,R21, R35, CD6), (A1, R19, R21, R35, CD7), (A1, R19, R22, R31, CD1), (A1,R19, R22, R31, CD2), (A1, R19, R22, R31, CD3), (A1, R19, R22, R31, CD4),(A1, R19, R22, R31, CD5), (A1, R19, R22, R31, CD6), (A1, R19, R22, R31,CD7), (A1, R19, R22, R32, CD1), (A1, R19, R22, R32, CD2), (A1, R19, R22,R32, CD3), (A1, R19, R22, R32, CD4), (A1, R19, R22, R32, CD5), (A1, R19,R22, R32, CD6), (A1, R19, R22, R32, CD7), (A1, R19, R22, R33, CD1), (A1,R19, R22, R33, CD2), (A1, R19, R22, R33, CD3), (A1, R19, R22, R33, CD4),(A1, R19, R22, R33, CD5), (A1, R19, R22, R33, CD6), (A1, R19, R22, R33,CD7), (A1, R19, R22, R34, CD1), (A1, R19, R22, R34, CD2), (A1, R19, R22,R34, CD3), (A1, R19, R22, R34, CD4), (A1, R19, R22, R34, CD5), (A1, R19,R22, R34, CD6), (A1, R19, R22, R34, CD7), (A1, R19, R22, R35, CD1), (A1,R19, R22, R35, CD2), (A1, R19, R22, R35, CD3), 1, R19, R22, R35, CD4),(A1, R19, R22, R35, CD5), (A1, R19, R22, R35, CD6), (A1, R19, R22, R35,CD7), (A1, R19, R23, R31, CD1), (A1, R19, R23, R31, CD2), (A1, R19, R23,R31, CD3), (A1, R19, R23, R31, CD4), (A1, R19, R23, R31, CD5), (A1, R19,R23, R31, CD6), (A1, R19, R23, R31, CD7), (A1, R19, R23, R32, CD1), (A1,R19, R23, R32, CD2), (A1, R19, R23, R32, CD3), (A1, R19, R23, R32, CD4),(A1, R19, R23, R32, CD5), (A1, R19, R23, R32, CD6), (A1, R19, R23, R32,CD7), (A1, R19, R23, R33, CD1), (A1, R19, R23, R33, CD2), (A1, R19, R23,R33, CD3), (A1, R19, R23, R33, CD4), (A1, R19, R23, R33, CD5), (A1, R19,R23, R33, CD6), (A1, R19, R23, R33, CD7), (A1, R19, R23, R34, CD1), (A1,R19, R23, R34, CD2), (A1, R19, R23, R34, CD3), (A1, R19, R23, R34, CD4),(A1, R19, R23, R34, CD5), (A1, R19, R23, R34, CD6), (A1, R19, R23, R34,CD7), (A1, R19, R23, R35, CD1), (A1, R19, R23, R35, CD2), (A1, R19, R23,R35, CD3), (A1, R19, R23, R35, CD4), (A1, R19, R23, R35, CD5), (A1, R19,R23, R35, CD6), (A1, R19, R23, R35, CD7), (A1, R19, R24, R31, CD1), (A1,R19, R24, R31, CD2), (A1, R19, R24, R31, CD3), (A1, R19, R24, R31, CD4),(A1, R19, R24, R31, CD5), (A1, R19, R24, R31, CD6), (A1, R19, R24, R31,CD7), (A1, R19, R24, R32, CD1), (A1, R19, R24, R32, CD2), (A1, R19, R24,R32, CD3), (A1, R19, R24, R32, CD4), (A1, R19, R24, R32, CD5), (A1, R19,R24, R32, CD6), (A1, R19, R24, R32, CD7), (A1, R19, R24, R33, CD1), (A1,R19, R24, R33, CD2), (A1, R19, R24, R33, CD3), (A1, R19, R24, R33, CD4),(A1, R19, R24, R33, CD5), (A1, R19, R24, R33, CD6), (A1, R19, R24, R33,CD7), (A1, R19, R24, R34, CD1), (A1, R19, R24, R34, CD2), (A1, R19, R24,R34, CD3), (A1, R19, R24, R34, CD4), (A1, R19, R24, R34, CD5), (A1, R19,R24, R34, CD6), (A1, R19, R24, R34, CD7), (A1, R19, R24, R35, CD1), (A1,R19, R24, R35, CD2), (A1, R19, R24, R35, CD3), (A1, R19, R24, R35, CD4),(A1, R19, R24, R35, CD5), (A1, R19, R24, R35, CD6), (A1, R19, R24, R35,CD7), (A1, R19, R25, R31, CD1), (A1, R19, R25, R31, CD2), A1, R19, R25,R31, CD3), A1, R19, R25, R31, CD4), (A1, R19, R25, R31, CD5), (A1, R19,R25, R31, CD6), (A1, R19, R25, R31, CD7), (A1, R19, R25, R32, CD1), (A1,R19, R25, R32, CD2), (A1, R19, R25, R32, CD3), (A1, R19, R25, R32, CD4),(A1, R19, R25, R32, CD5), (A1, R19, R25, R32, CD6), (A1, R19, R25, R32,CD7), (A1, R19, R25, R33, CD1), (A1, R19, R25, R33, CD2), (A1, R19, R25,R33, CD3), (A1, R19, R25, R33, CD4), (A1, R19, R25, R33, CD5), (A1, R19,R25, R33, CD6), (A1, R19, R25, R33, CD7), (A1, R19, R25, R34, CD1), (A1,R19, R25, R34, CD2), (A1, R19, R25, R34, CD3), (A1, R19, R25, R34, CD4),(A1, R19, R25, R34, CD5), (A1, R19, R25, R34, CD6), (A1, R19, R25, R34,CD7), (A1, R19, R25, R35, CD1), (A1, R19, R25, R35, CD2), (A1, R19, R25,R35, CD3), (A1, R19, R25, R35, CD4), (A1, R19, R25, R35, CD5), (A1, R19,R25, R35, CD6), (A1, R19, R25, R35, CD7), (A1, R19, R26, R31, CD1), (A1,R19, R26, R31, CD2), (A1, R19, R26, R31, CD3), (A1, R19, R26, R31, CD4),(A1, R19, R26, R31, CD5), (A1, R19, R26, R31, CD6), (A1, R19, R26, R31,CD7), (A1, R19, R26, R32, CD1), (A1, R19, R26, R32, CD2), (A1, R19, R26,R32, CD3), (A1, R19, R26, R32, CD4), (A1, R19, R26, R32, CD5), (A1, R19,R26, R32, CD6), (A1, R19, R26, R32, CD7), (A1, R19, R26, R33, CD1), (A1,R19, R26, R33, CD2), (A1, R19, R26, R33, CD3), (A1, R19, R26, R33, CD4),(A1, R19, R26, R33, CD5), (A1, R19, R26, R33, CD6), (A1, R19, R26, R33,CD7), (A1, R19, R26, R34, CD1), (A1, R19, R26, R34, CD2), (A1, R19, R26,R34, CD3), (A1, R19, R26, R34, CD4), (A1, R19, R26, R34, CD5), (A1, R19,R26, R34, CD6), (A1, R19, R26, R34, CD7), (A1, R19, R26, R35, CD1), (A1,R19, R26, R35, CD2), (A1, R19, R26, R35, CD3), (A1, R19, R26, R35, CD4),(A1, R19, R26, R35, CD5), (A1, R19, R26, R35, CD6), (A1, R19, R26, R35,CD7),(A2, R11, R21, R31, CD1), (A2, R11, R21, R31, CD2), (A2, R11, R21, R31,CD3), (A2, R11, R21, R31, CD4), (A2, R11, R21, R31, CD5), (A2, R11, R21,R31, CD6), (A2, R11, R21, R31, CD7), (A2, R11, R21, R32, CD1), (A2, R11,R21, R32, CD2), (A2, R11, R21, R32, CD3), (A2, R11, R21, R32, CD4), (A2,R11, R21, R32, CD5), (A2, R11, R21, R32, CD6), (A2, R11, R21, R32, CD7),(A2, R11, R21, R33, CD1), (A2, R11, R21, R33, CD2), (A2, R11, R21, R33,CD3), (A2, R11, R21, R33, CD4), (A2, R11, R21, R33, CD5), (A2, R11, R21,R33, CD6), (A2, R11, R21, R33, CD7), (A2, R11, R21, R34, CD1), (A2, R11,R21, R34, CD2), (A2, R11, R21, R34, CD3), (A2, R11, R21, R34, CD4), (A2,R11, R21, R34, CD5), (A2, R11, R21, R34, CD6), (A2, R11, R21, R34, CD7),(A2, R11, R21, R35, CD1), (A2, R11, R21, R35, CD2), (A2, R11, R21, R35,CD3), (A2, R11, R21, R35, CD4), (A2, R11, R21, R35, CD5), (A2, R11, R21,R35, CD6), (A2, R11, R21, R35, CD7), (A2, R11, R22, R31, CD1), (A2, R11,R22, R31, CD2), (A2, R11, R22, R31, CD3), (A2, R11, R22, R31, CD4), (A2,R11, R22, R31, CD5), (A2, R11, R22, R31, CD6), (A2, R11, R22, R31, CD7),(A2, R11, R22, R32, CD1), (A2, R11, R22, R32, CD2), (A2, R11, R22, R32,CD3), (A2, R11, R22, R32, CD4), (A2, R11, R22, R32, CD5), (A2, R11, R22,R32, CD6), (A2, R11, R22, R32, CD7), (A2, R11, R22, R33, CD1), (A2, R11,R22, R33, CD2), (A2, R11, R22, R33, CD3), (A2, R11, R22, R33, CD4), (A2,R11, R22, R33, CD5), (A2, R11, R22, R33, CD6), (A2, R11, R22, R33, CD7),(A2, R11, R22, R34, CD1), (A2, R11, R22, R34, CD2), (A2, R11, R22, R34,CD3), (A2, R11, R22, R34, CD4), (A2, R11, R22, R34, C 15), (A2, R11,R22, R34, CD6), (A2, R11, R22, R34, CD7), (A2, R11, R22, R35, CD1), (A2,R11, R22, R35, CD2), (A2, R11, R22, R35, CD3), (A2, R11, R22, R35, CD4),(A2, R11, R22, R35, CD5), (A2, R11, R22, R35, CD6), (A2, R11, R22, R35,CD7), (A2, R11, R23, R31, CD1), (A2, R11, R23, R31, CD2), (A2, R11, R23,R31, CD3), (A2, R11, R23, R31, CD4), (A2, R11, R23, R31, CD5), (A2, R11,R23, R31, CD6), (A2, R11, R23, R31, CD7), (A2, R11, R23, R32, CD1), (A2,R11, R23, R32, CD2), (A2, R11, R23, R32, CD3), (A2, R11, R23, R32, CD4),(A2, R11, R23, R32, CD5), (A2, R11, R23, R32, CD6), (A2, R11, R23, R32,CD7), (A2, R11, R23, R33, CD1), (A2, R11, R23, R33, CD2), (A2, R11, R23,R33, CD3), (A2, R11, R23, R33, CD4), (A2, R11, R23, R33, CD5), (A2, R11,R23, R33, CD6), (A2, R11, R23, R33, CD7), (A2, R11, R23, R34, CD1), (A2,R11, R23, R34, CD2), (A2, R11, R23, R34, CD3), (A2, R11, R23, R34, CD4),(A2, R11, R23, R34, CD5), (A2, R11, R23, R34, CD6), (A2, R11, R23, R34,CD7), (A2, R11, R23, R35, CD1), (A2, R11, R23, R35, CD2), (A2, R11, R23,R35, CD3), (A2, R11, R23, R35, CD4), (A2, R11, R23, R35, CD5), (A2, R11,R23, R35, CD6), (A2, R11, R23, R35, CD7), (A2, R11, R24, R31, CD1), (A2,R11, R24, R31, CD2), (A2, R11, R24, R31, CD3), (A2, R11, R24, R31, CD4),(A2, R11, R24, R31, CD5), (A2, R11, R24, R31, CD6), (A2, R11, R24, R31,CD7), (A2, R11, R24, R32, CD1), (A2, R11, R24, R32, CD2), (A2, R11, R24,R32, CD3), (A2, R11, R24, R32, CD4), (A2, R11, R24, R32, CD5), (A2, R11,R24, R32, CD6), (A2, R11, R24, R32, CD7), (A2, R11, R24, R33, CD1), (A2,R11, R24, R33, CD2), (A2, R11, R24, R33, CD3), (A2, R11, R24, R33, CD4),(A2, R11, R24, R33, CD5), (A2, R11, R24, R33, CD6), (A2, R11, R24, R33,CD7), (A2, R11, R24, R34, CD1), (A2, R11, R24, R34, CD2), (A2, R11, R24,R34, CD3), (A2, R11, R24, R34, CD4), (A2, R11, R24, R34, CD5), (A2, R11,R24, R34, CD6), (A2, R11, R24, R34, CD7), (A2, R11, R24, R35, CD1), (A2,R11, R24, R35, CD2), (A2, R11, R24, R35, CD3), (A2, R11, R24, R35, CD4),(A2, R11, R24, R35, CD5), (A2, R11, R24, R35, CD6), (A2, R11, R24, R35,CD7), (A2, R11, R25, R31, CD1), (A2, R11, R25, R31, CD2), (A2, R11, R25,R31, CD3), (A2, R11, R25, R31, CD4), (A2, R11, R25, R31, CD5), (A2, R11,R25, R31, CD6), (A2, R11, R25, R31, CD7), (A2, R11, R25, R32, CD1), (A2,R11, R25, R32, CD2), (A2, R11, R25, R32, CD3), (A2, R11, R25, R32, CD4),(A2, R11, R25, R32, CD5), (A2, R11, R25, R32, CD6), (A2, R11, R25, R32,CD7), (A2, R11, R25, R33, CD1), (A2, R11, R25, R33, CD2), (A2, R11, R25,R33, CD3), (A2, R11, R25, R33, CD4), (A2, R11, R25, R33, CD5), (A2, R11,R25, R33, CD6), (A2, R11, R25, R33, CD7), (A2, R11, R25, R34, CD1), (A2,R11, R25, R34, CD2), (A2, R11, R25, R34, CD3), (A2, R11, R25, R34, CD4),(A2, R11, R25, R34, CD5), (A2, R11, R25, R34, CD6), (A2, R11, R25, R34,CD7), (A2, R11, R25, R35, CD1), (A2, R11, R25, R35, CD2), (A2, R11, R25,R35, CD3), (A2, R11, R25, R35, CD4), (A2, R11, R25, R35, CD5), (A2, R11,R25, R35, CD6), (A2, R11, R25, R35, CD7), (A2, R11, R26, R31, CD1), (A2,R11, R26, R31, CD2), (A2, R11, R26, R31, CD3), (A2, R11, R26, R31, CD4),(A2, R11, R26, R31, CD5), (A2, R11, R26, R31, CD6), (A2, R11, R26, R31,CD7), (A2, R11, R26, R32, CD1), (A2, R11, R26, R32, CD2), (A2, R11, R26,R32, CD3), (A2, R11, R26, R32, CD4), (A2, R11, R26, R32, CD5), (A2, R11,R26, R32, CD6), (A2, R11, R26, R32, CD7), (A2, R11, R26, R33, CD1), (A2,R11, R26, R33, CD2), (A2, R11, R26, R33, CD3), (A2, R11, R26, R33, CD4),(A2, R11, R26, R33, CD5), (A2, R11, R26, R33, CD6), (A2, R11, R26, R33,CD7), (A2, R11, R26, R34, CD1), (A2, R11, R26, R34, CD2), (A2, R11, R26,R34, CD3), (A2, R11, R26, R34, CD4), (A2, R11, R26, R34, CD5), (A2, R11,R26, R34, CD6), (A2, R11, R26, R34, CD7), (A2, R11, R26, R35, CD1), (A2,R11, R26, R35, CD2), (A2, R11, R26, R35, CD3), (A2, R11, R26, R35, CD4),(A2, R11, R26, R35, CD5), (A2, R11, R26, R35, CD6), A2, R11, R26, R35,CD7), (A2, R12, R21, R31, CD1), (A2, R12, R21, R31, CD2), (A2, R12, R21,R31, CD3), (A2, R12, R21, R31, CD4), (A2, R12, R21, R31, CD5), (A2, R12,R21, R31, CD6), (A2, R12, R21, R31, CD7), (A2, R12, R21, R32, CD1), (A2,R12, R21, R32, CD2), (A2, R12, R21, R32, CD3), (A2, R12, R21, R32, CD4),(A2, R12, R21, R32, CD5), (A2, R12, R21, R32, CD6), (A2, R12, R21, R32,CD7), (A2, R12, R21, R33, CD1), (A2, R12, R21, R33, CD2), (A2, R12, R21,R33, CD3), (A2, R12, R21, R33, CD4), (A2, R12, R21, R33, CD5), (A2, R12,R21, R33, CD6), (A2, R12, R21, R33, CD7), (A2, R12, R21, R34, CD1), (A2,R12, R21, R34, CD2), (A2, R12, R21, R34, CD3), (A2, R12, R21, R34, CD4),(A2, R12, R21, R34, CD5), (A2, R12, R21, R34, CD6), (A2, R12, R21, R34,CD7), (A2, R12, R21, R35, CD1), (A2, R12, R21, R35, CD2), (A2, R12, R21,R35, CD3), (A2, R12, R21, R35, CD4), (A2, R12, R21, R35, CD5), (A2, R12,R21, R35, CD6), (A2, R12, R21, R35, CD7), (A2, R12, R22, R31, CD1), (A2,R12, R22, R31, CD2), (A2, R12, R22, R31, CD3), (A2, R12, R22, R31, CD4),(A2, R12, R22, R31, CD5), (A2, R12, R22, R31, CD6), (A2, R12, R22, R31,CD7), (A2, R12, R22, R32, CD1), (A2, R12, R22, R32, CD2), (A2, R12, R22,R32, CD3), (A2, R12, R22, R32, CD4), (A2, R12, R22, R32, CD5), (A2, R12,R22, R32, CD6), (A2, R12, R22, R32, CD7), (A2, R12, R22, R33, CD1), (A2,R12, R22, R33, CD2), (A2, R12, R22, R33, CD3), (A2, R12, R22, R33, CD4),(A2, R12, R22, R33, CD5), (A2, R12, R22, R33, CD6), (A2, R12, R22, R33,CD7), (A2, R12, R22, R34, CD1), (A2, R12, R22, R34, CD2), (A2, R12, R22,R34, CD 3), (A2, R12, R22, R34, CD4), (A2, R12, R22, R34, CD5), (A2,R12, R22, R34, CD6), (A2, R12, R22, R34, CD7), (A2, R12, R22, R35, CD1),(A2, R12, R22, R35, CD2), (A2, R12, R22, R35, CD3), (A2, R12, R22, R35,CD4), (A2, R12, R22, R35, CD5), (A2, R12, R22, R35, CD6), (A2, R12, R22,R35, CD7), (A2, R12, R23, R31, CD1), (A2, R12, R23, R31, CD2), (A2, R12,R23, R31, CD3), (A2, R12, R23, R31, CD4), (A2, R12, R23, R31, CD5), (A2,R12, R23, R31, CD6), (A2, R12, R23, R31, CD7), (A2, R12, R23, R32, CD1),(A2, R12, R23, R32, CD2), (A2, R12, R23, R32, CD3), (A2, R12, R23, R32,CD4), (A2, R12, R23, R32, CD5), (A2, R12, R23, R32, CD6), (A2, R12, R23,R32, CD7), (A2, R12, R23, R33, CD1), (A2, R12, R23, R33, CD2), (A2, R12,R23, R33, CD3), (A2, R12, R23, R33, CD4), (A2, R12, R23, R33, CD5), (A2,R12, R23, R33, CD6), (A2, R12, R23, R33, CD7), (A2, R12, R23, R34, CD1),(A2, R12, R23, R34, CD2), (A2, R12, R23, R34, CD3), (A2, R12, R23, R34,CD4), (A2, R12, R23, R34, CD5), (A2, R12, R23, R34, CD6), (A2, R12, R23,R34, CD7), (A2, R12, R23, R35, CD1), (A2, R12, R23, R35, CD2), (A2, R12,R23, R35, CD3), (A2, R12, R23, R35, CD4), (A2, R12, R23, R35, CD5), (A2,R12, R23, R35, CD6), (A2, R12, R23, R35, CD7), (A2, R12, R24, R31, CD1),(A2, R12, R24, R31, CD2), (A2, R12, R24, R31, CD3), (A2, R12, R24, R31,CD4), (A2, R12, R24, R31, CD5), (A2, R12, R24, R31, CD6), (A2, R12, R24,R31, CD7), (A2, R12, R24, R32, CD1), A2, R12, R24, R32, CD2), (A2, R12,R24, R32, CD3), (A2, R12, R24, R32, CD4), (A2, R12, R24, R32, CD5), (A2,R12, R24, R32, CD6), (A2, R12, R24, R32, CD7), (A2, R12, R24, R33, CD1),(A2, R12, R24, R33, CD2), (A2, R12, R24, R33, CD3), (A2, R12, R24, R33,CD4), (A2, R12, R24, R33, CD5), (A2, R12, R24, R33, CD6), (A2, R12, R24,R33, CD7), (A2, R12, R24, R34, CD1), (A2, R12, R24, R34, CD2), (A2, R12,R24, R34, CD3), (A2, R12, R24, R34, CD4), (A2, R12, R24, R34, CD 5),(A2, R12, R24, R34, CD6), (A2, R12, R24, R34, CD7), (A2, R12, R24, R35,CD1), (A2, R12, R24, R35, CD2), (A2, R12, R24, R35, CD3), (A2, R12, R24,R35, CD4), (A2, R12, R24, R35, CD5), (A2, R12, R24, R35, CD6), (A2, R12,R24, R35, CD7), (A2, R12, R25, R31, CD1), (A2, R12, R25, R31, CD2), (A2,R12, R25, R31, CD3), (A2, R12, R25, R31, CD4), (A2, R12, R25, R31, CD5),(A2, R12, R25, R31, CD6), (A2, R12, R25, R31, CD7), (A2, R12, R25, R32,CD1), (A2, R12, R25, R32, CD2), (A2, R12, R25, R32, CD3), (A2, R12, R25,R32, CD4), (A2, R12, R25, R32, CD5), (A2, R12, R25, R32, CD6), (A2, R12,R25, R32, CD7), (A2, R12, R25, R33, CD1), (A2, R12, R25, R33, CD2), (A2,R12, R25, R33, CD3), (A2, R12, R25, R33, CD 4), (A2, R12, R25, R33,CD5), (A2, R12, R25, R33, CD6), (A2, R12, R25, R33, CD7), (A2, R12, R25,R34, CD1), (A2, R12, R25, R34, CD2), (A2, R12, R25, R34, CD3), (A2, R12,R25, R34, CD4), (A2, R12, R25, R34, CD5), (A2, R12, R25, R34, CD6), (A2,R12, R25, R34, CD7), (A2, R12, R25, R35, CD1), (A2, R12, R25, R35, CD2),(A2, R12, R25, R35, CD3), (A2, R12, R25, R35, CD4), (A2, R12, R25, R35,CD5), (A2, R12, R25, R35, CD6), (A2, R12, R25, R35, CD7), (A2, R12, R26,R31, CD1), (A2, R12, R26, R31, CD2), (A2, R12, R26, R31, CD3), (A2, R12,R26, R31, CD4), (A2, R12, R26, R31, CD5), (A2, R12, R26, R31, CD6), (A2,R12, R26, R31, CD7), (A2, R12, R26, R32, CD1), (A2, R12, R26, R32, CD2),(A2, R12, R26, R32, CD3), (A2, R12, R26, R32, CD4), (A2, R12, R26, R32,CD5), (A2, R12, R26, R32, CD6), (A2, R12, R26, R32, CD7), (A2, R12, R26,R33, CD1), (A2, R12, R26, R33, CD2), (A2, R12, R26, R33, CD3), (A2, R12,R26, R33, CD4), (A2, R12, R26, R33, CD5), (A2, R12, R26, R33, CD6), (A2,R12, R26, R33, CD7), (A2, R12, R26, R34, CD1), (A2, R12, R26, R34, CD2),(A2, R12, R26, R34, CD3), (A2, R12, R26, R34, CD4), (A2, R12, R26, R34,CD5), (A2, R12, R26, R34, CD6), (A2, R12, R26, R34, CD7), (A2, R12, R26,R35, CD1), (A2, R12, R26, R35, CD2), (A2, R12, R26, R35, CD3), (A2, R12,R26, R35, CD4), (A2, R12, R26, R35, CD5), (A2, R12, R26, R35, CD6), (A2,R12, R26, R35, CD7), (A2, R13, R21, R31, CD1), (A2, R13, R21, R31, CD2),(A2, R13, R21, R31, CD3), (A2, R13, R21, R31, CD4), (A2, R13, R21, R31,CD5), (A2, R13, R21, R31, CD6), (A2, R13, R21, R31, CD7), (A2, R13, R21,R32, CD1), (A2, R13, R21, R32, CD2), (A2, R13, R21, R32, CD3), (A2, R13,R21, R32, CD4), (A2, R13, R21, R32, CD5), (A2, R13, R21, R32, CD6), (A2,R13, R21, R32, CD7), (A2, R13, R21, R33, CD1), (A2, R13, R21, R33, CD2),(A2, R13, R21, R33, CD3), (A2, R13, R21, R33, CD4), (A2, R13, R21, R33,CD5), (A2, R13, R21, R33, CD6), (A2, R13, R21, R33, CD7), (A2, R13, R21,R34, CD1), (A2, R13, R21, R34, CD2), (A2, R13, R21, R34, CD3), (A2, R13,R21, R34, CD4), (A2, R13, R21, R34, CD5), (A2, R13, R21, R34, CD6), (A2,R13, R21, R34, CD7), (A2, R13, R21, R35, CD1), (A2, R13, R21, R35, CD2),(A2, R13, R21, R35, CD3), (A2, R13, R21, R35, CD4), (A2, R13, R21, R35,CD5), (A2, R13, R21, R35, CD6), (A2, R13, R21, R35, CD7), (A2, R13, R22,R31, CD1), (A2, R13, R22, R31, CD2), (A2, R13, R22, R31, CD3), (A2, R13,R22, R31, CD4), (A2, R13, R22, R31, CD5), (A2, R13, R22, R31, CD6), (A2,R13, R22, R31, CD7), (A2, R13, R22, R32, CD1), (A2, R13, R22, R32, CD2),(A2, R13, R22, R32, CD3), (A2, R13, R22, R32, CD4), (A2, R13, R22, R32,CD5), (A2, R13, R22, R32, CD6), (A2, R13, R22, R32, CD7), (A2, R13, R22,R33, CD1), (A2, R13, R22, R33, CD2), (A2, R13, R22, R33, CD3), (A2, R13,R22, R33, CD4), (A2, R13, R22, R33, CD5), (A2, R13, R22, R33, CD6), (A2,R13, R22, R33, CD7), (A2, R13, R22, R34, CD1), (A2, R13, R22, R34, CD2),(A2, R13, R22, R34, CD3), (A2, R13, R22, R34, CD4), (A2, R13, R22, R34,CD5), (A2, R13, R22, R34, CD6), (A2, R13, R22, R34, CD7), (A2, R13, R22,R35, CD1), (A2, R13, R22, R35, CD2), (A2, R13, R22, R35, CD3), (A2, R13,R22, R35, CD4), (A2, R13, R22, R35, CD5), (A2, R13, R22, R35, CD6), (A2,R13, R22, R35, CD7), (A2, R13, R23, R31, CD1), (A2, R13, R23, R31, CD2),(A2, R13, R23, R31, CD3), (A2, R13, R23, R31, CD4), (A2, R13, R23, R31,CD5), (A2, R13, R23, R31, CD6), (A2, R13, R23, R31, CD7), (A2, R13, R23,R32, CD1), (A2, R13, R23, R32, CD2), (A2, R13, R23, R32, CD3), (A2, R13,R23, R32, CD4), (A2, R13, R23, R32, CD5), (A2, R13, R23, R32, CD6), (A2,R13, R23, R32, CD7), (A2, R13, R23, R33, CD1), (A2, R13, R23, R33, CD2),(A2, R13, R23, R33, CD3), (A2, R13, R23, R33, CD4), (A2, R13, R23, R33,CD5), (A2, R13, R23, R33, CD6), (A2, R13, R23, R33, CD7), (A2, R13, R23,R34, CD1), (A2, R13, R23, R34, CD2), (A2, R13, R23, R34, CD3), (A2, R13,R23, R34, CD4), (A2, R13, R23, R34, CD5), (A2, R13, R23, R34, CD6), (A2,R13, R23, R34, CD7), (A2, R13, R23, R35, CD1), (A2, R13, R23, R35, CD2),(A2, R13, R23, R35, CD3), (A2, R13, R23, R35, CD4), (A2, R13, R23, R35,CD5), (A2, R13, R23, R35, CD6), (A2, R13, R23, R35, CD7), (A2, R13, R24,R31, CD1), (A2, R13, R24, R31, CD2), (A2, R13, R24, R31, CD3), (A2, R13,R24, R31, CD4), (A2, R13, R24, R31, CD5), (A2, R13, R24, R31, CD6), (A2,R13, R24, R31, CD7), (A2, R13, R24, R32, CD1), (A2, R13, R24, R32, CD2),(A2, R13, R24, R32, CD3), (A2, R13, R24, R32, CD4), (A2, R13, R24, R32,CD5), (A2, R13, R24, R32, CD6), (A2, R13, R24, R32, CD7), (A2, R13, R24,R33, CD1), (A2, R13, R24, R33, CD2), (A2, R13, R24, R33, CD3), (A2, R13,R24, R33, CD4), (A2, R13, R24, R33, CD5), (A2, R13, R24, R38, CD6), (A2,R12, R24, R32, CD7), (A2, R13, R24, R34, CD1), (A2, R13, R24, R34, CD2),(A2, R13, R24, R34, CD3), (A2, R13, R24, R34, CD4), (A2, R13, R24, R34,CD5), (A2, R13, R24, R34, CD6), (A2, R13, R24, R34, CD7), (A2, R13, R24,R35, CD1), (A2, R13, R24, R35, CD2), (A2, R13, R24, R35, CD3), (A2, R13,R24, R35, CD4), (A2, R13, R24, R35, CD5), (A2, R13, R24, R35, CD6), (A2,R13, R24, R35, CD7), (A2, R13, R25, R31, CD1), (A2, R13, R25, R31, CD2),(A2, R13, R25, R31, CD3), (A2, R13, R25, R31, CD4), (A2, R13, R25, R31,CD5), (A2, R13, R25, R31, CD6), (A2, R13, R25, R31, CD7), (A2, R13, R25,R32, CD1), (A2, R13, R25, R32, CD2), (A2, R13, R25, R32, CD3), (A2, R13,R25, R32, CD4), (A2, R13, R25, R32, CD5), (A2, R13, R25, R32, CD6), (A2,R13, R25, R32, CD7), (A2, R13, R25, R33, CD1), (A2, R13, R25, R33, CD2),(A2, R13, R25, R33, CD3), (A2, R13, R25, R33, CD4), (A2, R13, R25, R33,CD5), (A2, R13, R25, R33, CD6), (A2, R13, R25, R33, CD7), (A2, R13, R25,R34, CD1), (A2, R13, R25, R34, CD2), (A2, R13, R25, R34, CD3), (A2, R13,R25, R34, CD4), (A2, R13, R25, R34, CD5), (A2, R13, R25, R34, CD6), (A2,R13, R25, R34, CD7), (A2, R13, R25, R35, CD1), (A2, R13, R25, R35, CD2),(A2, R13, R25, R35, CD3), (A2, R13, R25, R35, CD4), (A2, R13, R25, R35,CD5), (A2, R13, R25, R35, CD6), (A2, R13, R25, R35, CD7), (A2, R13, R26,R31, CD1), (A2, R13, R26, R31, CD2), (A2, R13, R26, R31, CD3), (A2, R13,R26, R31, CD4), (A2, R13, R26, R31, CD5), (A2, R13, R26, R31, CD6), (A2,R13, R26, R31, CD7), (A2, R13, R26, R32, CD1), (A2, R13, R26, R32, CD2),(A2, R13, R26, R32, CD3), (A2, R13, R26, R32, CD4), (A2, R13, R26, R32,CD5), (A2, R13, R26, R32, CD6), (A2, R13, R26, R32, CD7), (A2, R13, R26,R33, CD1), (A2, R13, R26, R33, CD2), (A2, R13, R26, R33, CD3), (A2, R13,R26, R33, CD4), (A2, R13, R26, R33, CD5), (A2, R13, R26, R33, CD6), (A2,R13, R26, R33, CD7), (A2, R13, R26, R34, CD1), (A2, R13, R26, R34, CD2),(A2, R13, R26, R34, CD3), (A2, R13, R26, R34, CD4), (A2, R13, R26, R34,CD5), (A2, R13, R26, R34, CD6), (A2, R13, R26, R34, CD7), (A2, R13, R26,R35, CD1), (A2, R13, R26, R35, CD2), (A2, R13, R26, R35, CD3), (A2, R13,R26, R35, CD4), (A2, R13, R26, R35, CD5), (A2, R13, R26, R35, CD6), (A2,R13, R26, R35, CD7), (A2, R14, R21, R31, CD1), (A2, R14, R21, R31, CD2),(A2, R14, R21, R31, CD3), (A2, R14, R21, R31, CD4), (A2, R14, R21, R31,CD5), (A2, R14, R21, R31, CD6), (A2, R14, R21, R31, CD7), (A2, R14, R21,R32, CD1), (A2, R14, R21, R32, CD2), (A2, R14, R21, R32, CD3), (A2, R14,R21, R32, CD4), (A2, R14, R21, R32, CD5), (A2, R14, R21, R32, CD6), (A2,R14, R21, R32, CD7), (A2, R14, R21, R33, CD1), (A2, R14, R21, R33, CD2),(A2, R14, R21, R33, CD3), (A2, R14, R21, R33, CD4), (A2, R14, R21, R33,CD5), (A2, R14, R21, R33, CD6), (A2, R14, R21, R33, CD7), (A2, R14, R21,R34, CD1), (A2, R14, R21, R34, CD2), (A2, R14, R21, R34, CD3), (A2, R14,R21, R34, CD4), (A2, R14, R21, R34, CD5), (A2, R14, R21, R34, CD6), (A2,R14, R21, R34, CD7), (A2, R14, R21, R35, CD1), (A2, R14, R21, R35, CD2),(A2, R14, R21, R35, CD3), (A2, R14, R21, R35, CD4), (A2, R14, R21, R35,CD5), (A2, R14, R21, R35, CD6), (A2, R14, R21, R35, CD7), (A2, R14, R22,R31, CD1), (A2, R14, R22, R31, CD2), (A2, R14, R22, R31, CD3), (A2, R14,R22, R31, CD4), (A2, R14, R22, R31, CD5), (A2, R14, R22, R31, CD6), (A2,R14, R22, R31, CD7), (A2, R14, R22, R32, CD1), (A2, R14, R22, R32, CD2),(A2, R14, R22, R32, CD3), (A2, R14, R22, R32, CD4), (A2, R14, R22, R32,CD5), (A2, R14, R22, R32, CD6), (A2, R14, R22, R32, CD7), (A2, R14, R22,R33, CD1), (A2, R14, R22, R33, CD2), (A2, R14, R22, R33, CD3), (A2, R14,R22, R33, CD4), (A2, R14, R22, R33, CD5), (A2, R14, R22, R33, 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R35, CD1), (A2, R16, R22, R35, CD2), (A2, R16, R22, R35, CD3),(A2, R16, R22, R85, CD4), (A2, R16, R22, R35, CD5), (A2, R16, R22, R35,CD6), (A2, R16, R22, R35, CD7), (A2, R16, R23, R31, CD1), (A2, R16, R23,R31, CD2), (A2, R16, R23, R31, CD3), (A2, R16, R23, R31, CD4), (A2, R16,R23, R31, CD5), (A2, R16, R23, R31, CD6), (A2, R16, R23, R31, CD7), (A2,R16, R23, R32, CD1), (A2, R16, R23, R32, CD2), (A2, R16, R23, R32, CD3),(A2, R16, R23, R32, CD4), (A2, R16, R23, R32, CD5), (A2, R16, R23, R32,CD6), (A2, R16, R23, R32, CD7), (A2, R16, R23, R33, CD1), (A2, R16, R23,R33, CD2), (A2, R16, R23, R33, CD3), (A2, R16, R23, R33, CD4), (A2, R16,R23, R33, CD5), (A2, R16, R23, R33, CD6), (A2, R16, R23, R33, CD7), (A2,R16, R23, R34, CD1), (A2, R16, R23, R34, CD2), (A2, R16, R23, R34, CD3),(A2, R16, R23, R34, CD4), (A2, R16, R23, R34, CD 5), (A2, R16, R23, R34,CD6), (A2, R16, R23, R34, CD7), (A2, R16, R23, R35, CD1), (A2, R16, R23,R35, CD2), (A2, R16, R23, R35, CD3), (A2, R16, R23, R35, CD4), (A2, R16,R23, 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R16,R25, R31, CD2), (A2, R16, R25, R31, CD3), (A2, R16, R25, R31, CD4), (A2,R16, R25, R31, CD5), (A2, R16, R25, R31, CD6), (A2, R16, R25, R31, CD7),(A2, R16, R25, R32, CD1), (A2, R16, R25, R32, CD2), (A2, R16, R25, R32,CD3), (A2, R16, R25, R32, CD4), (A2, R16, R25, R32, CD5), (A2, R16, R25,R32, CD6), (A2, R16, R25, R32, CD7), (A2, R16, R25, R33, CD1), (A2, R16,R25, R33, CD2), (A2, R16, R25, R33, CD3), (A2, R16, R25, R33, CD4), (A2,R16, R25, R33, CD5), (A2, R16, R25, R33, CD6), (A2, R16, R25, R33, CD7),(A2, R16, R25, R34, CD1), (A2, R16, R25, R34, CD2), (A2, R16, R25, R34,CD3), (A2, R16, R25, R34, CD4), (A2, R16, R25, R34, CD5), (A2, R16, R25,R34, CD6), (A2, R16, R25, R34, CD7), (A2, R16, R25, R35, CD1), (A2, R16,R25, R35, CD2), (A2, R16, R25, R35, CD 3), (A2, R16, R25, R35, CD4),(A2, R16, R25, R35, CD5), (A2, R16, R25, R35, CD6), (A2, R16, R25, R35,CD7), (A2, R16, R26, R31, CD1), (A2, R16, R26, R31, CD2), (A2, R16, R26,R31, CD3), (A2, R16, R26, R31, CD4), (A2, R16, R26, R31, CD5), (A2, R16,R26, R31, CD6), (A2, R16, R26, R31, CD7), (A2, R16, R26, R32, CD1), (A2,R16, R26, R32, CD2), (A2, R16, R26, R32, CD3), (A2, R16, R26, R32, CD4),(A2, R16, R26, R32, CD5), (A2, R16, R26, R32, CD6), (A2, R16, R26, R32,CD7), (A2, R16, R26, R33, CD1), (A2, R16, R26, R33, CD2), (A2, R16, R26,R33, CD3), (A2, R16, R26, R33, CD4), (A2, R16, R26, R33, CD5), (A2, R16,R26, R33, CD6), (A2, R16, R26, R33, CD7), (A2, R16, R26, R34, CD1), (A2,R16, R26, R34, CD2), (A2, R16, R26, R34, CD3), (A2, R16, R26, R34, CD4),(A2, R16, R26, R34, CD5), (A2, R16, R26, R34, CD6), (A2, R16, R26, R34,CD7), (A2, R16, R26, R35, CD1), (A2, R16, R26, R35, CD2), (A2, R16, R26,R35, CD3), (A2, R16, R26, R35, CD4), (A2, R16, R26, R35, CD5), (A2, R16,R26, R35, CD6), (A2, R16, R26, R35, CD7), (A2, R17, R21, R31, CD1), (A2,R17, R21, R31, CD2), (A2, R17, R21, R31, CD3), (A2, R17, R21, R31, CD4),(A2, R17, R21, R31, CD5), (A2, R17, R21, R31, CD6), (A2, R17, R21, R31,CD7), (A2, R17, R21, R32, CD1), (A2, R17, R21, R32, CD2), (A2, R17, R21,R32, CD3), (A2, R17, R21, R32, CD4), (A2, R17, R21, R32, CD5), (A2, R17,R21, R32, CD6), (A2, R17, R21, R32, CD7), (A2, R17, R21, R33, CD1), (A2,R17, R21, R33, CD2), (A2, R17, R21, R33, CD3), (A2, R17, R21, R33, CD4),(A2, R17, R21, R33, CD5), (A2, R17, R21, R33, CD6), (A2, R17, R21, R33,CD7), (A2, R17, R21, R34, CD1), (A2, R17, R21, R34, CD2), (A2, R17, R21,R34, CD3), (A2, R17, R21, R34, CD4), (A2, R17, R21, R34, CD5), (A2, R17,R21, R34, CD6), (A2, R17, R21, R34, CD7), (A2, R17, R21, R35, CD (A2,R17, R21, R35, CD2), (A2, R17, R21, R35, CD3), (A2, R17, R21, R35, CD4),(A2, R17, R21, R35, CD5), (A2, R17, R21, R35, CD6), (A2, R17, R21, R35,CD7), (A2, R17, R22, R31, CD1), (A2, R17, R22, R31, CD2), (A2, R17, R22,R31, CD3), (A2, R17, R22, R31, CD4), (A2, R17, R22, R31, CD5), (A2, R17,R22, R31, CD6), (A2, R17, R22, R31, CD7), (A2, R17, R22, R32, CD1), (A2,R17, R22, R32, CD2), (A2, R17, R22, R32, CD3), (A2, R17, R22, R32, CD4),(A2, R17, R22, R32, CD5), (A2, R17, R22, R32, CD6), (A2, R17, R22, R32,CD7), (A2, R17, R22, R33, CD1), (A2, R17, R22, R33, CD2), (A2, R17, R22,R33, CD3), (A2, R17, R22, R33, CD4), (A2, R17, R22, R33, CD5), (A2, R17,R22, R33, CD6), (A2, R17, R22, R33, CD7), (A2, R17, R22, R34, CD1), (A2,R17, R22, R34, CD2), (A2, R17, R22, R34, CD3), (A2, R17, R22, R34, CD4),(A2, R17, R22, R34, CD5), (A2, R17, R22, R34, CD6), (A2, R17, R22, R34,CD7), (A2, R17, R22, R35, CD1), (A2, R17, R22, R35, CD2), (A2, R17, R22,R35, CD3), (A2, R17, R22, R35, CD4), (A2, R17, R22, R35, CD5), (A2, R17,R22, R35, CD6), (A2, R17, R22, R35, CD7), (A2, R17, R23, R31, CD1), (A2,R17, R23, R31, CD2), (A2, R17, R23, R31, CD3), (A2, R17, R23, R31, CD4),(A2, R17, R23, R31, CD5), (A2, R17, R23, R31, CD6), (A2, R17, R23, R31,CD7), (A2, R17, R23, R32, CD1), (A2, R17, R23, R32, CD2), (A2, R17, R23,R32, CD3), (A2, R17, R23, R32, CD4), (A2, R17, R23, R32, CD5), (A2, R17,R23, R32, CD6), (A2, R17, R23, R32, CD7), (A2, R17, R23, R33, CD1), (A2,R17, R23, R33, CD2), (A2, R17, R23, R33, CD3), (A2, R17, R23, R33, CD4),(A2, R17, R23, R33, CD5), (A2, R17, R23, R33, CD6), (A2, R17, R23, R33,CD7), (A2, R17, R23, R34, CD1), (A2, R17, R23, R34, CD2), (A2, R17, R23,R34, CD3), (A2, R17, R23, R34, CD4), (A2, R17, R23, R34, CD5), (A2, R17,R23, R34, CD6), (A2, R17, R23, R34, CD7), (A2, R17, R23, R35, CD1), (A2,R17, R23, R35, CD2), (A2, R17, R23, R35, CD3), (A2, R17, R23, R35, CD4),(A2, R17, R23, R35, CD5), (A2, R17, R23, R35, CD6), (A2, R17, R23, R35,CD7), (A2, R17, R24, R31, CD1), (A2, R17, R24, R31, CD2), (A2, R17, R24,R31, CD3), (A2, R17, R24, R31, CD4), (A2, R17, R24, R31, CD5), (A2, R17,R24, R31, CD6), (A2, R17, R24, R31, CD7), (A2, R17, R24, R32, CD1), (A2,R17, R24, R32, CD2), (A2, R17, R24, R32, CD3), (A2, R17, R24, R32, CD4),(A2, R17, R24, R32, CD5), (A2, R17, R24, R32, CD6), (A2, R17, R24, R32,CD7), (A2, R17, R24, R33, CD1), (A2, R17, R24, R33, CD2), (A2, R17, R24,R33, CD3), (A2, R17, R24, R33, CD4), (A2, R17, R24, R33, CD5), (A2, R17,R24, R33, CD6), (A2, R17, R24, R33, CD7), (A2, R17, R24, R34, CD (A2,R17, R24, R34, CD2), (A2, R17, R24, R34, CD3), (A2, R17, R24, R34, CD4),(A2, R17, R24, R34, CD5), (A2, R17, R24, R34, CD6), (A2, R17, R24, R34,CD7), (A2, R17, R24, R35, CD1), (A2, R17, R24, R35, CD2), (A2, R17, R24,R35, CD3), (A2, R17, R24, R35, CD4), (A2, R17, R24, R35, CD5), (A2, R17,R24, R35, CD6), (A2, R17, R24, R35, CD7), (A2, R17, R25, R31, CD1), (A2,R17, R25, R31, CD2), (A2, R17, R25, R31, CD3), (A2, R17, R25, R31, CD4),(A2, R17, R25, R31, CD5), (A2, R17, R25, R31, CD6), (A2, R17, R25, R31,CD7), (A2, R17, R25, R32, CD1), (A2, R17, R25, R32, CD2), (A2, R17, R25,R32, CD3), (A2, R17, R25, R32, CD4), (A2, R17, R25, R32, CD5), (A2, R17,R25, R32, CD6), (A2, R17, R25, R32, CD7), (A2, R17, R25, R33, CD1), (A2,R17, R25, R33, CD2), (A2, R17, R25, R33, CD3), (A2, R17, R25, R33, CD4),(A2, R17, R25, R33, CD5), (A2, R17, R25, R33, CD6), (A2, R17, R25, R33,CD7), (A2, R17, R25, R34, CD1), (A2, R17, R25, R34, CD2), (A2, R17, R25,R34, CD3), (A2, R17, R25, R34, CD4), (A2, R17, R25, R34, CD5), (A2, R17,R25, R34, CD6), (A2, R17, R25, R34, CD7), (A2, R17, R25, R35, CD1), (A2,R17, R25, R35, CD2), (A2, R17, R25, R35, CD3), (A2, R17, R25, R35, CD4),(A2, R17, R25, R35, CD5), (A2, R17, R25, R35, CD6), (A2, R17, R25, R35,CD7), (A2, R17, R26, R31, CD1), (A2, R17, R26, R31, CD2), (A2, R17, R26,R31, CD3), (A2, R17, R26, R31, CD4), (A2, R17, R26, R31, CD5), (A2, R17,R26, R31, CD6), (A2, R17, R26, R31, CD7), (A2, R17, R26, R32, CD1), (A2,R17, R26, R32, CD2), (A2, R17, R26, R32, CD3), (A2, R17, R26, R32, CD4),(A2, R17, R26, R32, CD5), (A2, R17, R26, R32, CD6), (A2, R17, R26, R32,CD7), (A2, R17, R26, R33, CD1), (A2, R17, R26, R33, CD 2), (A2, R17,R26, R33, CD3), (A2, R17, R26, R33, CD4), (A2, R17, R26, R33, CD5), (A2,R17, R26, R33, CD6), (A2, R17, R26, R33, CD7), (A2, R17, R26, R34, CD1),(A2, R17, R26, R34, CD2), (A2, R17, R26, R34, CD3), (A2, R17, R26, R34,CD4), (A2, R17, R26, R34, CD5), (A2, R17, R26, R34, CD6), (A2, R17, R26,R34, CD7), (A2, R17, R26, R35, CD1), (A2, R17, R26, R35, CD2), (A2, R17,R26, R35, CD3), (A2, R17, R26, R35, CD4), (A2, R17, R26, R35, CD5), (A2,R17, R26, R35, CD6), (A2, R17, R26, R35, CD7), (A2, R18, R21, R31, CD1),(A2, R18, R21, R31, CD2), (A2, R18, R21, R31, CD3), (A2, R18, R21, R31,CD4), (A2, R18, R21, R31, CD5), (A2, R18, R21, R31, CD6), (A2, R18, R21,R31, CD7), (A2, R18, R21, R32, CD1), (A2, R18, R21, R32, CD2), (A2, R18,R21, R32, CD3), (A2, R18, R21, R32, CD4), (A2, R18, R21, R32, CD5), (A2,R18, R21, R32, CD6), (A2, R18, R21, R32, CD7), (A2, R18, R21, R33, CD1),(A2, R18, R21, R33, CD2), (A2, R18, R21, R33, CD3), (A2, R18, R21, R33,CD4), (A2, R18, R21, R33, CD5), (A2, R18, R21, R33, CD6), (A2, R18, R21,R33, CD7), (A2, R18, R21, R34, CD1), (A2, R18, R21, R34, CD2), (A2, R18,R21, R34, CD3), (A2, R18, R21, R34, CD4), (A2, R18, R21, R34, CD5), (A2,R18, R21, R34, CD6), (A2, R18, R21, R34, CD7), (A2, R18, R21, R35, CD1),(A2, R18, R21, R35, CD2), (A2, R18, R21, R35, CD3), (A2, R18, R21, R35,CD4), (A2, R18, R21, R35, CD5), (A2, R18, R21, R35, CD6), (A2, R18, R21,R35, CD7), (A2, R18, R22, R31, CD1), (A2, R18, R22, R31, CD2), (A2, R18,R22, R31, CD3), (A2, R18, R22, R31, CD4), (A2, R18, R22, R31, CD5), (A2,R18, R22, R31, CD6), (A2, R18, R22, R31, CD7), (A2, R18, R22, R32, CD1),(A2, R18, R22, R32, CD2), (A2, R18, R22, R32, CD3), (A2, R18, R22, R32,CD4), (A2, R18, R22, R32, CD5), (A2, R18, R22, R32, CD6), (A2, R18, R22,R32, CD7), (A2, R18, R22, R33, CD1), (A2, R18, R22, R33, CD2), (A2, R18,R22, R33, CD3), (A2, R18, R22, R33, CD4), (A2, R18, R22, R33, CD5), (A2,R18, R22, R33, CD6), (A2, R18, R22, R33, CD7), (A2, R18, R22, R34, CD1),(A2, R18, R22, R34, CD2), (A2, R18, R22, R34, CD3), (A2, R18, R22, R34,CD4), (A2, R18, R22, R34, CD5), (A2, R18, R22, R34, CD6), (A2, R18, R22,R34, CD7), (A2, R18, R22, R35, CD1), (A2, R18, R22, R35, CD2), (A2, R18,R22, R35, CD 3), (A2, R18, R22, R35, CD4), (A2, R18, R22, R35, CD 5),(A2, R18, R22, R35, CD6), (A2, R18, R22, R35, CD7), (A2, R18, R23, R31,CD1), (A2, R18, R23, R31, CD2), (A2, R18, R23, R31, CD3), (A2, R18, R23,R31, CD4), (A2, R18, R23, R31, CD5), (A2, R18, R23, R31, CD6), (A2, R18,R23, R31, CD7), (A2, R18, R23, R32, CD1), (A2, R18, R23, R32, CD2), (A2,R18, R23, R32, CD3), (A2, R18, R23, R32, CD4), (A2, R18, R23, R32, CD5),(A2, R18, R23, R32, CD6), (A2, R18, R23, R32, CD7), (A2, R18, R23, R33,CD1), (A2, R18, R23, R33, CD2), (A2, R18, R23, R33, CD3), (A2, R18, R23,R33, CD4), (A2, R18, R23, R33, CD5), (A2, R18, R23, R33, CD6), (A2, R18,R23, R33, CD7), (A2, R18, R23, R34, CD1), (A2, R18, R23, R34, CD2), (A2,R18, R23, R34, CD3), (A2, R18, R23, R34, CD4), (A2, R18, R23, R34, CD5),(A2, R18, R23, R34, CD6), (A2, R18, R23, R34, CD7), (A2, R18, R23, R35,CD1), (A2, R18, R23, R35, CD2), (A2, R18, R23, R35, CD3), (A2, R18, R23,R35, CD4), (A2, R18, R23, R35, CD5), (A2, R18, R23, R35, CD6), (A2, R18,R23, R35, CD7), (A2, R18, R24, R31, CD1), (A2, R18, R24, R31, CD2), (A2,R18, R24, R31, CD3), (A2, R18, R24, R31, CD4), (A2, R18, R24, R31, CD5),(A2, R18, R24, R31, CD6), (A2, R18, R24, R31, CD7), (A2, R18, R24, R32,CD1), (A2, R18, R24, R32, CD2), (A2, R18, R24, R32, CD3), (A2, R18, R24,R32, CD4), (A2, R18, R24, R32, CD5), (A2, R18, R24, R32, CD6), (A2, R18,R24, R32, CD7), (A2, R18, R24, R33, CD1), (A2, R18, R24, R33, CD2), (A2,R18, R24, R33, CD3), (A2, R18, R24, R33, CD4), (A2, R18, R24, R33, CD5),(A2, R18, R24, R33, CD6), (A2, R18, R24, R33, CD7), (A2, R18, R24, R34,CD1), (A2, R18, R24, R34, CD2), (A2, R18, R24, R34, CD3), (A2, R18, R24,R34, CD4), (A2, R18, R24, R34, CD5), (A2, R18, R24, R34, CD6), (A2, R18,R24, R34, CD7), (A2, R18, R24, R35, CD1), (A2, R18, R24, R35, CD2), (A2,R18, R24, R35, CD3), (A2, R18, R24, R35, CD4), (A2, R18, R24, R35, CD5),(A2, R18, R24, R35, CD6), (A2, R18, R24, R35, CD7), (A2, R18, R25, R31,CD1), (A2, R18, R25, R31, CD2), (A2, R18, R25, R31, CD3), (A2, R18, R25,R31, CD4), (A2, R18, R25, R31, CD5), (A2, R18, R25, R31, CD6), (A2, R18,R25, R31, CD7), (A2, R18, R25, R32, CD1), (A2, R18, R25, R32, CD2), (A2,R18, R25, R32, CD3), 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R32, CD4), (A3, R19,R24, R32, CD5), (A3, R19, R24, R32, CD6), (A3, R19, R24, R32, CD7), (A3,R19, R24, R33, CD1), (A3, R19, R24, R33, CD2), (A3, R19, R24, R33, CD3),(A3, R19, R24, R33, CD4), (A3, R19, R24, R33, CD5), (A3, R19, R24, R33,CD6), (A3, R19, R24, R33, CD7), (A3, R19, R24, R34, CD1), (A3, R19, R24,R34, CD2), (A3, R19, R24, R34, CD3), (A3, R19, R24, R34, CD4), (A3, R19,R24, R34, CD5), (A3, R19, R24, R34, CD6), (A3, R19, R24, R34, CD7), (A3,R19, R24, R35, CD1), (A3, R19, R24, R35, CD2), (A3, R19, R24, R35, CD3),(A3, R19, R24, R35, CD4), (A3, R19, R24, R35, CD5), (A3, R19, R24, R35,CD6), (A3, R19, R24, R35, CD7), (A3, R19, R25, R31, CD1), (A3, R19, R25,R31, CD2), (A3, R19, R25, R31, CD3), (A3, R19, R25, R31, CD4), (A3, R19,R25, R31, CD5), (A3, R19, R25, R31, CD6), (A3, R19, R25, R31, CD7), (A3,R19, R25, R32, CD1), (A3, R19, R25, R32, CD2), (A3, R19, R25, R32, CD3),(A3, R19, R25, R32, CD4), (A3, R19, R25, R32, CD5), (A3, R19, R25, R32,CD6), (A3, R19, R25, R32, CD7), (A3, R19, R25, R33, CD1), (A3, R19, R25,R33, CD2), (A3, R19, R25, R33, CD3), (A3, R19, R25, R33, CD4), (A3, R19,R25, R33, CD5), (A3, R19, R25, R33, CD6), (A3, R19, R25, R33, CD7), (A3,R19, R25, R34, CD1), (A3, R19, R25, R34, CD2), (A3, R19, R25, R34, CD3),(A3, R19, R25, R34, CD4), (A3, R19, R25, R34, CD5), (A3, R19, R25, R34,CD6), (A3, R19, R25, R34, CD7), (A3, R19, R25, R35, CD1), (A3, R19, R25,R35, CD2), (A3, R19, R25, R35, CD3), (A3, R19, R25, R35, CD4), (A3, R19,R25, R35, CD5), (A3, R19, R25, R35, CD6), (A3, R19, R25, R35, CD7), (A3,R19, R26, R31, CD1), (A3, R19, R26, R31, CD2), (A3, R19, R26, R31, CD3),(A3, R19, R26, R31, CD4), (A3, R19, R26, R31, CD5), (A3, R19, R26, R31,CD6), (A3, R19, R26, R31, CD7), (A3, R19, R26, R32, CD1), (A3, R19, R26,R32, CD2), (A3, R19, R26, R32, CD3), (A3, R19, R26, R32, CD4), (A3, R19,R26, R32, CD5), (A3, R19, R26, R32, CD6), (A3, R19, R26, R32, CD7), (A3,R19, R26, R33, CD1), (A3, R19, R26, R33, CD2), (A3, R19, R26, R33, CD3),(A3, R19, R26, R33, CD4), (A3, R19, R26, R33, CD5), (A3, R19, R26, R33,CD6), (A3, R19, R26, R33, CD7), (A3, R19, R26, R34, CD1), (A3, R19, R26,R34, CD2), (A3, R19, R26, R34, CD5), (A3, R19, R26, R34, CD4), (A3, R19,R26, R34, CD5), (A3, R19, R26, R34, CD6), (A3, R19, R26, R34, CD7), (A3,R19, R26, R35, CD1), (A3, R19, R26, R35, CD2), (A3, R19, R26, R35, CD3),(A3, R19, R26, R35, CD4), (A3, R19, R26, R35, CD5), (A3, R19, R26, R35,CD6) or (A3, R19, R26, R35, CD7).

The compound of the present invention is useful against diseases inducedby production, secretion or deposition of amyloid-β proteins. Forexample, the compound is effective for treating and/or preventing, andameliorating symptoms of diseases such as dementia of the Alzheimer'stype (e.g. Alzheimer's disease and senile dementia of the Alzheimer'stype), Down syndrome, memory disorder, prion diseases (e.g.Creutzfeldt-Jakob disease), mild cognitive impairment (MCI), hereditarycerebral hemorrhage with amyloidosis-Dutch type, cerebral amyloidangiopathy, other degenerative dementia, vascular and degenerative mixeddementia, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcorticobasal degeneration, Alzheimer's disease with diffuse Lewy bodies,age-related macular degeneration, Parkinson's disease and amyloidangiopathy.

The compound of the present invention has a high inhibitory activity onBACE1 and/or high selectivity against other enzymes. Thus, the compoundcan be used as pharmaceuticals with reduced side effects. In addition,the compound of the present invention has various advantages such ashigh metabolic stability, high solubility, high oral absorbability, highbioavailability, good clearance, high brain transferability, a long halflife, high protein unbinding ratio, low hERG channel inhibition, low CYPinhibition and/or negative in Ames test.

When the compound according to the present invention is administered,other medicaments (e.g. other therapeutic agents for Alzheimer's diseasesuch as acetylcholine esterase) may be used in combination. For example,anti-dementia drugs such as donepezil hydrochloride, tacrine,galantamine, rivastigmine, zanapezil, memantine and vinpocetine may beused in combination.

When the compound according to the present invention is administered tohumans, it may be orally administered as powders, granules, tablets,capsules, pills, liquids and the like, or may be parenterallyadministered as injections, suppositories, transdermal systems, inhalantand the like. In addition, if needed, an effective amount of the presentcompound may be mixed with pharmaceutical additives such as diluents,binders, humectants, disintegrants and lubricants suitable for itsdosage form, and thereby the compound may be formed into apharmaceutical preparation.

The dosage depends on disease conditions, the route of administration,the age or the weight of a patient. In the case of oral administrationto adults, the dosage is generally 0.1 μg to 1 g/day, and preferably0.01 to 500 mg/day. In the case of parenteral administration, the dosageis generally 1 μg to 10 g/day, and preferably 0.1 to 5 g/day.

EXAMPLES

The present invention will be described in more detail with referenceto, but not limited to, the following examples and test examples.

In the examples, meaning of each abbreviation is as follows.

Me: methylEt: ethylPh: phenylBz: benzoylBn: benzylBooc t-butoxycarbonylMs: methanesulfonylHATU: O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate WSCD: water soluble carbodiimide(1-ethyl-3-(3-dimethyl amino propyl)carbodiimide)THF: tetrahydrofuranDMF: dimethyl formamide

Example 1 Synthesis of Compound 3

Step 1

Compound (1) (667 mg), HATU (1369 mg) and5-(2-butynyl)pyrazine-2-carboxylic acid (749 mg) were dissolved inN,N-dimethylformamide (10 ml) and triethylamine (628 μl) and stirred atroom temperature for 2 hours, Ethyl acetate was added to the solution,washed with potassium carbonate and brine, and dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas washed with methanol to afford Compound (2) (563 mg),

¹H-NMR (DMSO-d₆) δ: 1.40 (9H, s), 1.85 (3H, s), 4.13 (2H, d, J=5.56 Hz),5.09 (2H, d, J=2.02 Hz), 7.00 (1H, d, J=7.58 Hz), 7.30 (1H, t, J=7.83Hz), 7.37-7.40 (1H, m), 7.69 (1H, d, J=7.58 Hz), 7.79 (1H, s), 8.44 (1H,s), 8.89 (1H, s), 10.44 (1H, s).

Step 2

Compound (2) (382 mg) was dissolved in chloroform (16 ml),trifluoroacetic acid (2 ml) was added at room temperature, and themixture was stirred at room temperature for 2 hours. The solvent wasremoved under reduced pressure, ethyl acetate was added and the mixturewas washed with potassium carbonate and brine. After being removed thesolvent, the solid was collected by filtration to afford Compound (3)(207 mg).

¹H-NMR (DMSO-d₆) δ: 1.85 (3H, s), 3.71 (2H, s), 5.09 (2H, d, J=2.02 Hz),7.10 (1H, d, J=7.58 Hz), 7.28 (1H, t, J=7.58 Hz), 7.69 (1H, d, J=8.08Hz), 7.81 (1H, s), 8.44 (1H, s), 8.89 (1H, s), 10.37 (1H, s).

Step 3

Compound (3) (200 mg) was suspended in acetone (4 ml),benzoylisothiocyanate (100 μl) was added at room temperature and themixture was stirred for 90 minutes. The precipitated solid was collectedby filtration to afford Compound (4) (180 mg).

¹H-NMR (DMSO-d₆) δ: 1.85 (3H, s), 4.90 (2H, d, J=5.56 Hz), 5.09 (2H, d,J=2.02 Hz), 7.15 (1H, d, J=7.58 Hz), 7.36 (1H, t, J=7.83 Hz), 7.52 (2H,t, J=7.83 Hz), 7.64 (1H, t, J=7.33 Hz), 7.80 (1H, d, J=9.09 Hz), 7.94(3H, t, J=8.08 Hz), 8.44 (1H, s), 8.89 (1H, s), 10.51 (1H, s),11.25-11.28 (1H, m), 11.44 (1H, s).

Step 4

Compound (4) (171 mg) was suspended in methanol (5 ml), an aqueoussolution of sodium hydroxide (2 mol/l, 205 μl) was added at roomtemperature and the mixture was stirred for 3.5 hours. The precipitatedsolid was collected by filtration to afford Compound (5) (114 mg).

¹H-NMR (DMSO-d₆) δ: 1.86 (3H, s), 4.63 (2H, br s), 5.09 (2H, d, J=2.02Hz), 7.05 (1H, d, J=7.58 Hz), 7.09 (1H, br s), 7.32 (1H, t, J=8.08 Hz),7.72 (1H, d, J=7.07 Hz), 7.83 (1H, s), 8.00 (1H, br s), 8.44 (1H, s),8.90 (1H, s), 10.46 (1H, s).

Step 5

A solution (2 ml) of methane iodide (23.9 mg) in acetonitrile was addedto Compound (5) (50 mg) at room temperature and the mixture was heatedat 60° C. for about 5 hours. The solvent was removed under reducedpressure and ethyl acetate was added. The mixture was washed withpotassium carbonate and brine, dried over magnesium sulfate and thesolvent was removed under reduces pressure. The resulting residue waspurified by chromatography to afford Compound 3 (37.6 mg).

¹H-NMR (DMSO-d₆) δ: 1.86 (3H, br s), 2.28 (3H, s), 4.30 (2H, br s), 5.09(2H, d, J=2.03 Hz), 7.07-7.09 (1H, m), 7.28 (1H, t, J=7.86 Hz), 7.68(1H, d, J=8.11 Hz), 7.84 (1H, s), 8.44-8.45 (1H, m), 8.89-8.90 (1H, m),10.41 (1H, s).

Example 2 Synthesis of Compound 15

Step 1

Compound (6) (800 mg) was dissolved in diethyl ether (20 ml).Tetraisopropoxytitanium (1.32 ml) and a solution of ethylmagnesiumbromide in tetrahydrofuran (1 mol/l, 8.80 ml) to the mixture at −78° C.under nitrogen atmosphere. The mixture was stirred for 10 minutes,allowed to warm to room temperature and stirred for 50 minutes. Themixture was cooled with ice and diethyl ether complex of trifluoroborane(1.00 ml) was added. The mixture was allowed to warm to room temperatureand stirred for 60 minutes. The mixture was cooled with ice, an aqueoussolution of hydrochloric acid and extracted with diethyl ether. Theaqueous layer was neutralized with an aqueous solution of sodiumhydroxide and extracted with diethyl ether. The organic layer was washedwith brine, dried over magnesium sulfate and the solvent was removedunder reduced pressure to afford Compound (7) (389 mg).

¹H-NMR (CDCl₃) δ: 0.88-0.91 (2H, m), 1.00-1.02 (2H, m), 1.97 (2H, br s),6.90-6.95 (0H, m), 7.30-7.34 (1H, m), 7.42 (1H, dd, J=6.59, 2.53 Hz).

Step 2

Compound (7) (280 mg) was dissolved in acetone (6 ml). Benzoylisothiocyanate (66 μl) was added to the mixture at room temperature andthe mixture was stirred for 90 minutes. The solvent was removed underreduced pressure and the residue was purified by chromatography toafford Compound (8) (402 mg).

¹H NMR (DMSO-d₆) δ: 1.39 (4H, br s), 7.19 (1H, t, J=9.09 Hz), 7.48-7.52(3H, m), 7.61-7.65 (1H, m), 7.76-7.77 (1H, m), 7.90 (2H, d, J=7.58 Hz),11.36 (1H, br s), 11.50 (1H, s).

Step 3

Compound (8) (200 mg) was dissolved in methanol (4 ml). An aqueoussolution of sodium hydroxide (2 mol/l, 280 μl) was added to the mixtureat room temperature and the mixture was stirred for 60 minutes. Thesolvent was removed under reduced pressure and the residue was extractedwith ethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate and the solvent was removed under reduced pressure.The resulting residue was dissolved in acetonitrile (4 ml) and methaneiodide (108 mg) was added to the mixture at room temperature. Themixture was allowed to warm to 60° C. and stirred for 90 minutes. Thesolvent was removed under reduced pressure and the resulting residue wasdissolved in methanol (4 ml). Triethylamine (106 μl) and di-tert-butyldicarbonate (Boc₂O) (177 μl) were added to the mixture at roomtemperature and the mixture was stirred for 50 minutes. The solvent wasremoved under reduced pressure, ethyl acetate was added and insolubleresidue was filtered off. The solvent was removed again under reducedpressure and the resulting residue was purified by chromatography toafford Compound (9) (184 mg).

¹H-NMR (DMSO-d₆) δ: 1.32-1.41 (4H, m), 1.40 (9H, s), 2.29 (3H, s),7.18-7.22 (1H, m), 7.50-7.54 (1H, m), 7.61-7.65 (1H, m).

Step 4

Compound (9) (180 mg), tris(dibenzylidene acetone)di palladium (Pd₂(dba)₃) (61 mg) and butyl di-1-adamantyl phosphine (50 mg) weredissolved in toluene (3 ml), and stirred at room temperature undernitrogen atmosphere for 10 minutes. Then a solution of lithiumhexamethyl disilazide (LHMDS) in tetrahydrofuran (1 mol/l, 1.33 ml) wasadded to the mixture and stirred at 80° C. for about 3 hours. Then themixture was cooled with ice, diethyl ether (5 ml) and an aqueoussolution of hydrochloric acid (1 mol/l, 2.67 ml) were added to themixture and stirred for 15 minutes. The mixture was neutralized with anaqueous solution of potassium carbonate and extracted with ethylacetate. The organic layer was waned with brine and dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas purified with chromatography to afford Compound (10) (41 mg).

¹H-NMR (DMSO-d₆) δ: 1.25 (4H, d, J=23.24 Hz), 1.40 (9H, s), 2.28 (3H,s), 4.96 (2H, br s), 6.42-6.46 (1H, m), 6.58-6.62 (1H, m), 6.79-6.85(1H, m), 10.22 (1H, br s).

Step 5

Compound (10) (40 mg), HATU (30.8 mg) and5-(2-butynyl)pyrazine-2-carboxylic acid (15.5 mg) were dissolved inN,N-dimethylformamide (1 ml) and triethylamine (12 μl) and the mixturewas stirred at room temperature for 2 hours. Ethyl acetate was poured tothe mixture, the organic layer was washed with potassium carbonate andbrine, and dried over magnesium sulfate. The solvent was removed underreduced pressure, and the resulting residue was purified withchromatography. The obtained material was dissolved in dichloromethane(1 trifluoroacetic acid (0.2 ml) was added to the mixture at roomtemperature. The mixture was stirred at room temperature for about 3hours. Then the solvent was removed under reduced pressure and ethylacetate was added. The organic layer was washed with aq. potassiumcarbonate and brine and the residue was purified with chromatography toafford Compound 15 (14.9 mg).

¹H-NMR (DMSO-d₆) δ: 1.04 (2H, br s), 1.14 (2H, s), 1.86 (3H, s), 2.19(3H, s), 5.10 (2H, s), 7.09-7.13 (1H, m), 7.74-7.79 (1H, m), 7.98-8.04(1H, m), 8.45 (1H, s), 8.90 (1H, s), 10.49 (1H, s).

Example 3 Synthesis of Compound 20

Step 1

Compound (11) (2000 mg) was suspended in methanol (10 ml) andtetrahydrofuran (10 ml). 2 mol/l aqueous solution of sodium hydroxide(4.05 ml) was added the mixture and the mixture was stirred at roomtemperature for 2 hours. 2 mol/l aqueous solution of hydrochloric acid(4.1 ml) was added to the mixture and the solvent was removed underreduced pressure. The precipitated solid was collected by filtration toafford Compound (12) (2200 mg).

¹H-NMR (DMSO-d₆) δ: 1.51 (9H, s), 8.21-8.22 (1H, m), 8.42 (1H, s), 8.63(1H, s), 10.12 (1H, s), 13.66 (1H, br s).

Step 2

Compound (12) (900 mg) was dissolved in tetrahydrofuran (9 ml). Asolution of borane dimethyl sulfide complex in tetrahydrofuran (1.9mol/l, 2.5 ml) was added to the mixture and the mixture was heated withstirring at 50° C. for about 3 hours. Then a solution of borane dimethylsulfide complex in tetrahydrofuran (1.9 mol/l, 2.0 ml) was added to themixture again and the mixture was heated with stirring at 50° C. forabout additional 3 hours.

Methanol (3 ml) was added to the mixture and the solvent was removedunder reduced pressure. After addition of ethyl acetate, the organiclayer was washed with aq.sodium carbonate and brine, dried overmagnesium sulfate and the solvent was removed under reduced pressure.The resulting residue was purified by chromatography to afford Compound(13) (506.3 mg).

¹H NMR (DMSO-d₆) δ: 1.50 (9H, s), 4.56 (2H, d, J=5.58 Hz), 5.49 (1H, t,J=5.83 Hz), 7.79 (2H, d, J=9.12 Hz), 8.30 (1H, s), 9.89 (1H, s).

Step 3

Compound (13) (663 mg) and triphenyl phosphine (778 mg) were dissolvedin N,N-dimethyl formamide (3.3 ml). Carbon tetrabromide (984 mg) wasadded to the mixture and the mixture was stirred under nitrogenatmosphere at room temperature for about 2 hours. Then sodium azide (321mg) was added to the mixture and the mixture was stirred at roomtemperature for about 5 hours. Ethyl acetate was added to the reactionmixture and the organic layer was washed with aq.sodium carbonate andbrine. The organic layer was dried over magnesium sulfate and thesolvent was removed under reduced pressure. The resulting residue waspurified by chromatography to afford Compound (14) (579 mg).

¹H-NMR (DMSO-d₆) δ: 1.50 (9H, s), 4.62 (2H, s), 7.84 (2H, s), 8.38 (1H,s), 9.99 (1H, s).

Step 4

Compound (14) (300 mg) was dissolved in dichloromethane (4 ml),trifluoroacetic acid (1 ml) was added to the mixture and the mixture wasstirred at room temperature for about 2 hours. Then the solvent wasremoved under reduced pressure, ethyl acetate was added to the mixture.The organic layer was washed with potassium carbonate and brine. Theresulting residue was dissolved in dichloromethane (2 ml) and pyridine(0.7 ml). Methanesulfonyl chloride (218 mg) was added to the mixtureunder cooling with ice and the mixture was stirred at room temperaturefor about 4 hours. Ethyl acetate was added to the mixture and theorganic layer was washed with 1 mold hydrochloride and brine. Theorganic layer was dried over magnesium sulfate and the solvent wasremoved under reduced pressure. The resulting residue was purified bychromatography to afford Compound (15) (195 mg).

¹H-NMR (CDCl₃) δ: 3.14 (3H, s), 4.52 (2H, s), 5.30 (1H, s), 7.54 (1H,s), 8.00 (2H, s), 8.02 (2H, t, J=1.77 Hz).

Step 5

Compound (15) (195 mg) was dissolved in methanol (5 ml). 10% palladiumcarbon powders (containing 51.84% H₂O, 100 mg) was added, to the mixtureand the mixture was stirred at room temperature under hydrogenatmosphere overnight. The reaction mixture was filtrated and the solventwas removed under reduced pressure. The residue was suspended inisopropanol (3.24 ml) and conc. sulfuric acid (0.195 ml), and reacted ina microwave reactor (100° C., 15 minutes). Ethyl acetate was added tothe mixture and an insoluble material was collected by filtration toafford sulfate of Compound (16) (270.5 mg). Ethyl acetate was added to aportion of the material (166 mg) and the organic layer was washed withaq.sodium carbonate and brine, and dried over magnesium sulfate. Thesolvent was removed under reduced pressure to afford Compound (16) (105mg).

¹H-NMR (DMSO-d₆) δ: 3.01 (3H, s), 3.70 (2H, s), 6.86 (1H, s), 7.28 (1H,s), 7.44 (2H, d, J=8.62 Hz), 7.52-7.54 (3H, m), 8.01-8.04 (2H, m), 8.71(1H, s), 9.71 (1H, s).

Step 6

Compound (16) (105 mg) was dissolved in acetone (5 ml).Benzoylisothiocyanate (56.8 μl) was added to the mixture at roomtemperature and the mixture was stirred for about 4 hours. The solventwas removed under reduced pressure and the resulting residue waspurified by chromatography to afford Compound (17) (62.1 mg).

—NMR (DMSO-d₆) δ: 3.07 (3H, s), 4.87-4.90 (2H, m), 6.91 (1H, s), 7.30(1H, s), 7.49-7.65 (7H, m), 7.95 (2H, d, J=7.07 Hz), 8.02-8.05 (2H, m),8.71 (1H, s), 9.82 (1H, s), 9.88 (1H, s), 11.29 (1H, br s), 11.47 (1H,s).

Step 7

Compound (17) (62 mg) was suspended in methanol (2 ml). An aqueoussolution of sodium hydroxide (2 mol/l, 70 μl) was added to the mixtureat room temperature and the mixture was stirred for about 3.5 hours.Then the solvent was removed under reduced pressure and ethyl acetatewas added. The organic layer was washed with aq.potassium carbonate andbrine, dried over magnesium sulfate, and the solvent was removed underreduced pressure, a solution (2 ml) of iodomethane (19.8 mg) inacetonitrile was poured to the residue at room temperature and themixture was heated at 60° C. for about 5 hours. Then the solvent wasremoved under reduced pressure and ethyl acetate was added. The organiclayer was washed with aq.potassium carbonate and brine, dried overmagnesium sulfate and the solvent was removed under reduced pressure toafford Compound 20 (45.1 mg),

¹H-NMR (DMSO-d₆) δ: 2.30 (3H, s), 3.02 (3H, s), 4.26 (2H, s), 6.89 (1H,br s), 7.28-7.29 (1H, m), 7.42-7.57 (5H, m), 8.01-8.04 (2H, m), 8.70(1H, s), 9.72 (1H, s).

Example 4 Synthesis of Compound 24

Step 1

A known Compound (18) (10.32 g) was dissolved in pyridine (100 mL).O-methyl hydroxyamine hydrochloride (5.36 g) was added to the mixture atroom temperature and the mixture was stirred at 60° C. for about 3hours. Then the solvent was removed under reduced pressure, diethylether was added. The organic layer was washed with water and brine, anddried over sodium sulfate. The solvent was removed under reducedpressure to afford crude Compound (19) (12 g).

Step 2

The crude Compound (19) (556 mg) was dissolved in tetrahydrofuran (5.5mL). Borane/tetrahydrofuran solution (1 mol/L: 4.66 mL) was added to themixture at room temperature and the mixture was stirred at 70° C. for 7hours. After cooling to 0° C., water (5 mL) and 2 mol/l aqueous solutionof sodium hydroxide (10 mL) were added to the mixture and the mixturewas stirred at 70° C. overnight. After cooling to room temperature, themixture was extracted with hexane The organic layer was washed withbrine and dried over sodium sulfate. The resulting residue was purifiedby chromatography to afford Compound (20) (330 mg).

¹H-NMR (DMSO-d₆) δ: 8.30 (1H, s), 8.04 (1H, d, J=7.83 Hz), 7.82 (1H, d,J=7.83 Hz), 7.57 (1H, t, J=7.83 Hz), 7.33 (2H, d, J=8.34 Hz), 6.87 (2H,d, J=8.34 Hz), 5.21 (1H, s), 3.71 (3H, s).

Step 3

Compound (20) (215 mg) was dissolved in tetrahydrofuran (2 mL).Benzoylisothiocyanate (0.118 mL) was added to the mixture at 0° C. andthe mixture was stirred for 2.5 hours. Then the mixture was allowed towarm to room temperature. Methanol (1 mL) and 1 mol/l aqueous solutionof sodium hydroxide (0.916 mL) was added to the mixture and the mixturewas stirred at 50° C. for 1 hour. Tetrahydrofuran was removed underreduced pressure, the precipitated solid was collected by filtration andwashed with water to afford Compound (21) (233 mg).

¹H-NMR (DMSO-d₆) δ: 8.64 (1H, d, J=8.34 Hz), 8.13 (1H, d, J=8.34 Hz),8.08 (1H, s), 7.75-7.60 (2H, m), 7.20 (2H, d, J=7.58 Hz), 6.94 (2H, d,J=7.58 Hz), 6.67 (1H, br s), 3.74 (3H, s).

Step 4

Compound (21) (339 mg) was dissolved in acetonitrile (6 mL). Methaneiodide (0.08 mL) was added to the mixture at room temperature, and themixture was stirred at 50° C. for 3.5 hours. The reaction mixture wasallowed to cool to room temperature, methane iodide (0.02 mL) was addedand the mixture was stirred at 50° C. for 1 hour. The solvent wasremoved under reduced pressure. Methanol (3 mL), triethylamine (0.222mL), and di-tert-butyldicarbonate (Boc₂O) (0.297 mL) were added toresulting residue at room temperature and the mixture was stirred for3.5 hours. The solvent was removed under reduced pressure and theresidue was purified by chromatography to afford Compound (22) (406 mg).

¹H NMR (DMSO-d₆) δ: 8.19 (1H, s), 8.15 (1H, d, J=7.07 Hz), 7.80 (1H, d,J=7.07 Hz), 7.70-7.66 (1H, m), 7.28 (2H, d, J=7.33 Hz), 6.95 (2H, d,J=7.33 Hz), 6.33 (1H, br s), 3.74 (3H, s), 2.42 (3H, s), 1.39 (9H, s).

Step 5

Compound (22) (100 mg) was dissolved in methanol (1 mL), Tetrahydrofuran(1 mL) and water (0.5 mL), ammonium chloride (49.6 mg) and reduced iron(51.8 mg) were added to the mixture at room temperature, and the mixturewas stirred at 70° C. for 2.5 hours. The mixture was allowed to cool toroom temperature, ethyl acetate was added and the precipitated insolublematerial was filtered off. The filtrate was washed with brine to affordcrude Compound (23) (88 mg).

Step 6

Compound (23) (88.4 mg), HATU (100 mg) and5-methoxypyrazine-2-carboxylic acid (37.3 mg) were dissolved inN,N-dimethylformamide (2 mL). Triethylamine (0.046 mL) was added to themixture at room temperature, and the mixture was stirred for 2 hours. Anaqueous solution of ammonium chloride was added and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, and dried over sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by chromatography toafford Compound (24) (84 mg).

¹H-NMR (CDCl₃) δ: 10.47 (1H, s), 9.51 (1H, s), 9.01 (1H, s), 8.14 (1H,s), 7.83 (1H, d, J=7.07 Hz), 7.52 (1H, s), 7.37 (1H, t, J=7.07 Hz), 7.20(2H, d, J=8.34 Hz), 7.06 (1H, d, J=7.07 Hz), 6.88 (2H, d, J=8.34 Hz),5.93 (1H, s), 4.06 (3H, s), 3.79 (3H, s), 2.44 (3H, s), 1.51 (9H, s).

Step 7

Compound (24) (84 mg) was dissolved in chloroform (1 mL).Trifluoroacetic acid (1 mL) was added to the mixture at room temperatur,and the mixture was stirred for 1.5 hours. The solvent was removed underreduced pressure, then an aqueous solution of sodium carbonate wasadded. The aqueous layer was extracted with ethyl acetate. The organiclayer was washed with brine and dried over sodium sulfate. The solventwas removed under reduced pressure and the precipitated solid was washedwith diisopropyl ether to afford Compound 24 (44 mg).

¹H-NMR (CDCl₃) δ: 9.48 (1H, s), 9.00 (1H, s), 8.14 (1H, s), 7.75 (1H, d,J=7.83 Hz), 7.60 (1H, s), 7.34 (1H, t, J=7.83 Hz), 7.25-7.22 (2H, m),7.12-7.09 (1H, m), 6.85 (2H, d, J=7.33 Hz), 6.02 (1H, s), 4.06 (3H, s),3.78 (3H, s), 2.37 (3H, s).

Example 5 Synthesis of Compound 26

Step 1

Compound (25) (3.02 g) was dissolved in ethanol (40 ml), water (14 ml)and tetrahydrofuran (8.4 ml). Ammonium chloride (0.88 g) was added tothe mixture at room temperature and the mixture was stirred at 70° C.for 10 minutes. After iron (3.68 g) was added, the mixture was stirredfor 30 minutes at the same temperature, then allowed to warm to roomtemperature and stirred for additional 1.5 hours. The solvent wasconcentrated under reduced pressure, ethyl acetate was added and theorganic layer was washed with an aqueous solution of sodium carbonateand brine. The solvent was removed and the resulting solid was purifiedby recrystallization to afford Compound (26) (1.82 g).

¹H-NMR (CDCl₃) δ: 2.61 (dd, J=5.1, 0.4 Hz, 3H), 3.65 (br s, 2H), 6.80(dt, J=8.6, 3.5 Hz, 1H), 6.93 (dd, J=10.4, 8.8 Hz, 1H), 7.12 (dd, J=6.9,3.1 Hz,

Step 2

Compound (26) (1.82 g) was dissolved in dichloromethane (35 ml).Triethylamine (1.8 ml). t-Butyl carbonate (2.85 g) and 4-dimethyl aminopyridine (145 mg) were added to the mixture at room temperature and themixture was stirred at room temperature overnight. A saturated aqueoussolution of ammonium chloride was poured to the mixture, followed byethyl acetate. The organic layer was washed with water and brine, driedover sodium sulfate and the solvent was removed under reduced pressure.The resulting residue was purified by chromatography to afford Compound(27) (0.51 g).

¹H-NMR (CDCl₃) δ: 1.51 (s, 9H), 2.63 (d, J=4.9 Hz, 3H), 6.59 (s, 1H),7.08 (dd, J=10.1, 9.1 Hz, 1H), 7.63 (dd, J=6.2, 3.0 Hz, 1H), 7.76 (m,1H).

Step 3

Compound (27) (203 mg) was dissolved in methanol (1.5 ml) anddichloromethane (1.5 ml). Sodium borohydride (33.4 mg) was added to themixture under cooling with ice and the mixture was stirred for 30minutes. A saturated aqueous solution of ammonium chloride was poured tothe mixture, followed by ethyl acetate. The organic layer was washedwith water and brine, and dried over sodium sulfate. The solvent wasremoved under reduced pressure to afford Compound (28) (203 mg).

¹H-NMR (CDCl₃) δ: 1.43-1.58 (m, 12H), 1.95 (d, J=4.5 Hz, 1H), 5.15 (m,1H), 6.44 (s, 1H), 6.94 (t, J=9.4 Hz, 1H), 7.42 (dd, J=6.4, 2.6 Hz, 1H).

Step 4

Compound (28) (103.3 mg) was dissolved in dichloromethane (1 ml).Triethylamine (84 μl) and methanesulfonyl chloride (38 μl) were added tothe mixture at room temperature and the mixture was stirred for 1.5hours. Ethyl acetate was added and the organic layer was washed withwater and brine, dried over sodium sulfate and the solvent was removedunder reduced pressure.

The resulting residue was dissolved in dimethylformamide (1 ml). Sodiumazide (52.6 mg) was added to the mixture and the mixture was stirred at90° C. for 1 hour. Water was poured to the mixture, followed by ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate and the solvent was removed under reduced pressure. Theresulting residue was purified by chromatography to afford Compound (29)(81.5 mg).

¹H-NMR (CDCl₃) δ: 1.52-1.53 (m, 12H), 4.93 (q, J=6.8 Hz, 1H), 6.50 (s,1H), 6.99 (t, J=9.2 Hz, 1H), 7.28 (dd, J=8.5, 5.0 Hz, 1H), 7.37 (dd,J=6.3, 2.8 Hz, 1H).

Step 5

Compound (29) (115 mg) was dissolved in tetrahydrofuran (1.5 ml) andwater (0.15 ml). Triphenylphosphine (113 mg) was added to the mixture atroom temperature, and the mixture was stirred at 50° C. for 3 hours andat 70° C. for additional 1 hour. 10% aqueous solution of citric acid waspoured to the mixture, followed by and ethyl acetate. 10% Aqueoussolution of sodium hydrogencarbonate was added to an aqueous layer,followed by ethyl acetate. The organic layer was washed with water,dried over sodium sulfate and the solvent was removed under reducedpressure to afford Compound (30) (85.2 mg).

¹H-NMR (CDCl₃) δ: 1.41 (d, J=6.6 Hz, 3H), 1.51 (s, 9H), 1.81 (br s, 3H),4.35 (q, J=6.6 Hz, 1H), 6.47 (br s, 1H), 6.93 (t, J=9.5 Hz, 1H), 7.19(m, 1H), 7.40 (dd, J=6.3, 2.7 Hz, 1H).

Step 6

Compound (30) (85.2 mg) was dissolved in tetrahydrofuran (1 ml).Benzoylisothiocyanate (51 μl) was added to the mixture at roomtemperature, and the mixture was stirred for 30 minutes. The solvent wasremoved under reduced pressure and the resulting residue was purified bychromatography to afford Compound (31) (132 mg).

¹H-NMR (CDCl₃) δ: 1.50 (d, J=0.3 Hz, 9H), 1.66 (d, J=7.0 Hz, 3H), 1.72(s, 1H), 5.65-5.75 (m, 1H), 6.51 (s, 1H), 7.02 (t, J=9.5 Hz, 1H), 7.24(dd, J=6.4, 2.7 Hz, 1H), 7.36 (s, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.60-7.65(m, 1H), 7.81-7.86 (m, 2H), 8.99 (s, 1H), 11.23 (d, J=7.7 Hz, 1H).

Step 7

Compound (31) (131 mg) was dissolved in methanol (1.5 ml). An aqueoussolution of sodium hydroxide (1 mol/l, 347 μl) was added to the mixtureand the mixture was stirred at 50° C. for 25 minutes. Ethyl acetate wasadded to the mixture and the organic layer was washed with water andbrine, dried over sodium sulfate and the solvent was removed underreduced pressure.

The resulting residue was dissolved in acetonitrile (1.5 ml), methaneiodide (24 μl) was added at room temperature, and the mixture wasstirred at 60° C. for 3 hours. The solvent was removed under reducedpressure, and the resulting residue was purified by chromatography toafford Compound (32) (130 mg).

¹H-NMR (CDCl₃) δ: 1.51 (s, 10H), 1.67 (d, J=6.7 Hz, 3H), 2.70 (s, 3H),5.05 (q, J=6.6 Hz, 1H), 6.70 (s, 1H), 7.01 (t, J=9.2 Hz, 1H), 7.18 (dd,J=5.7, 2.3 Hz, 1H), 7.61 (s, 1H).

Step 8

Compound (32) (103 mg) was dissolved in chloroform (1.5 ml).Trifluoroacetic acid (1.5 ml) was added to the mixture at roomtemperature, and the mixture was stirred for 80 minutes. Water, 10%aqueous solution of sodium hydrogen carbonate and ethyl acetate wereadded to the mixture and the organic layer was washed with water andbrine, and dried over sodium sulfate. The solvent was removed underreduced pressure to afford Compound (33) (63.1 mg).

¹H-NMR (CD₃OD) δ: 1.43 (d, J=6.7 Hz, 3H), 2.38 (s, 3H), 4.89 (s, 6H),5.03 (q, J=6.8 Hz, 1H), 6.58 (ddd, J=8.6, 4.2, 2.9 Hz, 1H), 6.70 (dd,J=6.4, 2.9 Hz, 1H), 6.80 (dd, J=10.3, 8.6 Hz, 1H).

Step 9

Compound (33) (42.9 mg) and 5-methoxypyrazine-2-carboxylic acid (30.5mg) were dissolved in methanol (1 ml). Hydrochloric acid (2 mol/l, 94μl) and WSCD HCl (38.0 mg) were added to the mixture at room temperatureand the mixture was stirred for 1 hour. Water, 10% sodium hydrogencarbonate and ethyl acetate were added to the mixture, and the organiclayer was washed with water and brine, and dried over sodium sulfate.The solvent was removed under reduced pressure and the resulting residuewas purified by chromatography, followed by TLC to afford Compound 26(22.0 mg).

¹H-NMR (CDCl₃) δ: 1.58 (d, J=6.7 Hz, 3H), 2.46 (s, 3H), 4.06 (s, 3H),5.12-5.14 (m, 1H), 7.06 (t, J=9.5 Hz, 1H), 7.55 (dd, J=6.3, 2.7 Hz, 1H),7.81 (cit, J=10.3, 2.9 Hz, 1H), 8.14 (d, J=1.2 Hz, 1H), 8.99 (d, J=1.2Hz, 1H), 9.51 (s, 1H),

Example 6 Synthesis of Compound 28

Step 1

To a solution of Compound (34) (200 mg) in tetrahydrofuran (0.6 ml) wasadded benzoylisothiocyanate (151 μl) at 0° C. The mixture was stirredfor 10 minutes, Diisopropyl ether was added and the precipitated solidwas collected by filtration to afford Compound (35) (277 mg).

Step 2

To a solution of Compound (35) (277 mg) in tetrahydrofuran (0.83 ml) andmethanol (0.83 ml) was added 1 mol/l aqueous solution of sodiumhydroxide (0.83 ml). The mixture was stirred at room temperature for 1hour. Tetrahydrofuran was removed under reduced pressure and theprecipitated solid was collected by filtration. The solid was washedwith water and ethyl acetate to afford Compound (36) (81 mg).

Step 3

To a suspension of Compound (36) (81 mg) in methanol (2 ml) was addedmethane iodide (31 μl). The mixture was stirred at 40° C. for 1 hour.After addition of methane iodide (31 μl), the mixture was stirred at 60°C. for 2 hours. Moreover addition of methane iodide (62 μl) and stirringfor 3 hours. The solvent was removed under reduced pressure to affordCompound (37) (127 mg).

Step 4

To a solution of Compound (37) in acetic acid (1 ml) and methanol (2 ml)was added iron (91 mg) at 60° C. and the mixture was stirred for 1 hour.Ethyl acetate was added and the mixture was made alkaline with saturatedsodium hydrogen carbonate and insoluble material was filtered off. Theorganic layer of the filtrate was washed with saturated brine and driedover magnesium sulfate. The solvent was removed under reduced pressureto afford crude Compound (38).

Step 5

To a solution of the crude Compound (38) in methanol (2 ml), 2 mol/lhydrochloric acid (146 μl) were added 4-cyano pyridine-2-carboxylic acidmonohydrate (54 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (62 mg). The mixture was stirred at room temperature for 1hour, 1 mol/l aqueous solution of sodium hydroxide (400 μl) was added.The precipitated solid was collected by filtration and washed withwater. The solid was recrystallized from acetone to afford Compound 28(31 mg).

¹H-NMR (DMSO-d6) δ: 2.44 (3H, s), 6.40 (2H, s), 6.83 (1H, d, J=8.0 Hz),7.30 (1H, t, J=8.0 Hz), 7.45 (1H, d, J=8.0 Hz), 7.82 (1H, d J=8.0 Hz),7.92 (1H, d J=8.0 Hz), 8.31 (1H, d, J=8.0 Hz), 8.57 (2H, m), 9.20 (1H,s), 10.93 (1H, s).

Example 7 Synthesis of Compound 31

Step 1

Sodium hydride (2.85 g, 35.7 mmol) was suspended in dimethylsulfoxide(50 ml) and a solution of 2-(3-nitrophenyl)acetonitrile (Compound (39),5.26 g, 32.4 mmol) and 1,4-dibromobutane (4.23 ml, 35.7 mmol) indimethylsulfoxide/ethyl ether (50 ml/25 ml) was added dropwise below 35°C. over 25 minutes. Aftrer addition, the mixture was stirred at roomtemperature for 1.5 hours. The mixture was poured into ice water-2mol/1-hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with an aqueous solution of sodium hydrogen carbonateand water and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure and the residue was chromatographedon silica gel with ethyl acetate/n-hexane (1:5) as eluent. The eluentwas concentrated under reduced pressure to afford a pale brown Compound(40) (6.42 g, 92%).

¹H-NMR (CDCl₃) δ: 2.06-2.18 (6H, m), 2.15-2.62 (2H, m), 7.59 (1H, m),7.85 (1H, m), 8.19 (1H, m), 8.29 (1H, m)

Step 2

Compound (40) (3.5 g, 16.19 mmol) was suspended in 35 ml of sulfuricacid-water (1:1) and heated under reflux for 8 hours. The reactionmixture was poured into ice water, the precipitated solid was collectedby filtration, and air-dried to afford Compound (41) (3.59 g, 94%) as apale brown solid.

¹H-NMR (CDCl₃) δ: 1.72-2.03 (6H, m), 2.66-2.78 (2H, m), 7.49 (1H, m),7.72 (1H, m), 8.11 (1H, m), 8.25 (1H, m)

Step 3

Compound (41) (2.0 g, 8.50 mmol) was suspended in toluene (20 ml) andtriethylamine (1.77 ml, 12.75 mmol) and diphenylphosphoryl azide (2.02ml, 9.35 mmol) were added, followed by stirring at room temperature for35 minutes. After confirming disappearance of the starting material, thereaction mixture was stirred with heat at 100° C. for 35 minutes,followed by addition of methanol (5 ml), and the mixture was heated withstirring at 100° C. for 3 hours. The reaction mixture was poured intoice-water and extracted with ethyl acetate. The organic layer was washedwith water, dried over anhydrous sodium sulfate and the solvent wasconcentrated under reduced pressure. n-Hexane was added to the resultingresidue to yield Compound (42) (2.12 g, 94%) as a white solid.

¹H-NMR (CDCl₃) δ: 1.80-1.96 (4H, m), 1.98-2.34 (2H, m), 2.26-2.40 (2H,m), 3.57 (3H, s), 5.12 (1H, s), 7.48 (1H, m), 7.76 (1H, d, J=7.5 Hz),8.08 (1H, m), 8.26 (1H, m)

Step 4

Compound (42) (1.0 g, 3.78 mmol) was dissolved in dimethylsulfoxide (5ml) and 5 ml of 20% aqueous solution of lithium hydroxide was added. Thereaction mixture was heated with stirring at 110° C. for 2 hours. Themixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with water and dried over sodium sulfate. Thesolvent was concentrated under reduced pressure to afford Compound (43)(0.78 g, ˜100%) as a pale brown oil. Compound (21) was used in thefollowing reaction without purification.

¹H-NMR (CDCl₃) δ: 1.55 (2H, s), 1.80-2.10 (8H, m), 7.49 (1H, m), 7.82(1H, m), 8.07 (1H, m), 8.35 (1H, m)

Step 5

Compound (43) (0.78 g, 3.78 mmol) was dissolved in acetone (16 ml) andbenzoylisothiocyanate (0.61 ml, 4.54 mmol) was added at room temperatureand the mixture was stirred for 1 hour. The reaction mixture wasconcentrated under reduced pressure. After being removed an insolublematerial with chloroform, the residue was chromatographed on column withethyl acetate/n-hexane (1:5) as eluent. The eluent was concentratedunder reduced pressure to afford Compound (44) (1.3 g, 93%) as a paleyellow oil.

¹H-NMR (CDCl₃) δ: 1.86-2.04 (4H, m), 2.20-2.35 (2H, m), 2.60-2.73 (2H,m), 7.46-7.60 (3H, m), 7.65 (1H, m), 7.75 (1H, m), 7.82-7.88 (2H, m),8.11 (1H, m), 8.26 (1H, m), 8.83 (1H, s), 11.39 (1H, s).

Step 6

Compound (44) (1.3 g, 3.52 mmol) was dissolved in methanol (13 ml) and 1mol/l aqueous solution of sodium hydroxide (4.22 ml, 4.22 mmol) wasadded and heated with stirring at 50° C. for 10 minutes. The reactionmixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulfate andconcentrated under reduced pressure. The resulting residue wasrecrystallized from ethyl acetate/n-hexane (1:5) to afford Compound (45)(0.82 g, 88%) as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.85-2.35 (8H, m), 5.54 (2H, br s), 6.92 (1H, s), 7.60(1H, m), 7.83 (1H, m), 8.18 (1H, m), 8.26 (1H, m)

Step 7

Compound (45) (0.5 g, 1.88 mmol) was dissolved in acetonitrile (10 ml)and dimethyl sulfate (0.18 ml, 1.88 mmol) was added and heated withstirring at 50° C. for 2 hours. The reaction mixture was allowed to coolto room temperature, di-tert-butyl dicarbonate (0.41 g, 1.88 mmol) andtriethylamine (0.26 ml, 1.88 mmol) were added successively, and stirredat room temperature for 2.5 hours. The reaction mixture was poured intoice-water and extracted with ethyl acetate. The organic layer was washedwith water, dried over sodium sulfate and concentrated under reducedpressure. The residue was chromatographed on column using ethylacetate/n-hexane (1:5) as eluent, concentrated under reduced pressure toafford Compound (46) (0.7 g, 98%) as a white solid.

¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 1.80-2.04 (4H, m), 2.14-2.26 (2H, m),2.28 (3H, s), 2.30-2.42 (2H, m), 7.50 (1H, m), 7.72 (1H, m), 8.12 (1H,m), 8.23 (1H, m), 10.65 (1H, s).

Step 8

Compound (46) (0.3 g, 0.79 mmol) was dissolved in tetrahydrofuran (4 ml)and methanol (2 ml) and water (1 ml), ammonium chloride (106 mg, 1.98mmol), then iron powders (221 mg, 3.95 mmol) were added and the mixturewas heated to reflux for 3.5 hours. Insoluble material was filtered offand the filtrate was concentrated under reduced pressure to affordCompound (47) (300 mg, ˜100%) as a pale yellow foam. Compound (25) wasused in the following reaction without purification.

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 1.74-1.94 (4H, m), 2.10-2.30 (4H, m),2.29 (3H, s), 3.66 (2H, s), 6.57 (1H, m), 6.69 (1H, m), 6.75 (1H, m),7.10 (1H, m), 10.56 (1H, s).

Step 9

Compound (47) (105 mg, 0.3 mmol) was dissolved in ethyl acetate (2 ml)and 5-cyano picoline acid (monohydrate) (49.9 mg, 0.3 mmol),triethylamine (0.063 ml, 0.45 mmol) and diphenylphosphoryl chloride(0.062 ml, 0.3 mmol) were added successively, and the mixture wasstirred at room temperature for 50 minutes. The reaction mixture waspoured into ice-water and extracted with ethyl acetate. The organiclayer was washed with an aqueous solution of sodium hydrogen carbonateand water successively, and dried over sodium sulfate. The solvent wasconcentrated under reduced pressure, chromatographed on column usingethyl acetate/n-hexane (1:5) as eluent and concentrated under reducedpressure. The crude residue was purified by preparative TLC with ethylacetate/n-hexane (1:1) to ethyl acetate to afford Compound (48) (87 mg,60%) as a white oil.

¹H-NMR CDCl₃) δ: 1.55 (9H, s), 1.80-2.00 (4H, m), 2.16-2.38 (4H, m),2.27 (3H, s), 7.21 (1H, d, J=6.9 Hz), 7.38 (1H, m), 7.65 (1H, m), 7.84(1H, d, J=7.2 Hz), 8.21 (1H, dd, J=2.1, 8.4 Hz), 8.44 (1H, d, J=8.4 Hz),8.92 (1H, d, J=1.8 Hz), 9.88 (1H, s), 10.63 (1H, s).

Step 10

Compound (48) (87 mg, 0.18 mmol) was dissolved in formic acid (0.5 ml)and stirred at room temperature for 18 hours. The reaction mixture waspoured into ice-water and neutralized with an aqueous solution of sodiumhydrogen carbonate, then extracted with ethyl acetate. The organic layerwas washed with water, dried over sodium sulfate and concentrated underreduced pressure. The residue was recrystallized from ethylacetate/n-hexane (1:1) to afford Compound 31 (19 mg, 28%) as a whitepowder.

¹H-NMR (DMSO-d₆) δ: 1.66-1.86 (4H, m), 1.19-2.06 (2H, m), 2.24-2.36 (2H,m), 2.28 (3H, s), 7.13 (1H, d, J=8.4 Hz), 7.30 (1H, m), 7.77 (1H, d,J=8.7 Hz), 7.93 (1H, s), 8.28 (1H, dd, J=0.9, 8.1 Hz), 8.58 (1H, dd,J=2.1, 8.1 Hz), 9.19 (1H, m), 10.75 (1H, s),

Example 8 Synthesis of Compound 29

Step 1

To 1 mol/l solution of borane-tetrahydrofuran complex (3.70 ml, 3.70mmol) was added a solution of 1-(3-nitro phenyl)cyclopentanecarbonitrile (0.4 g, 1.85 mmol) (Compound (40): synthesized in Step 1)in tetrahydrofuran (2 ml) and heated to reflux for 2.5 hours. Afterquenching with methanol, the mixture was partitioned into ethyl acetateand an aqueous solution of sodium hydrogen carbonate. The organic layerwas washed with water and dried over sodium sulfate. The solvent wasconcentrated under reduced pressure and the residue was chromatographedon column with ethyl acetate/n-hexane (1:3) as eluent. The eluent wasconcentrated under reduced pressure to afford Compound (49) (128 mg,31%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.47 (2H, s), 1.68-2.08 (8H, m), 2.81 (2H, s), 7.49(1H, m), 7.62 (1H, m), 8.07 (1H, m), 8.14 (1H, m)

Step 2

Compound (49) (128 mg, 0.58 mmol) was dissolved in acetone (1 ml) andbenzoylisothiocyanate (0.094 ml, 0.70 mmol) was added at roomtemperature, and stirred for 30 minutes. The reaction mixture was pouredinto ice-water and extracted with ethyl acetate. The organic layer waswaked with water and dried over sodium sulfate. The solvent wasconcentrated under reduced pressure and the residue was chromatographedon column with ethyl acetate/n-hexane (1:3) as eluent. The eluent wasconcentrated under reduced pressure to afford Compound (50) (110 mg,49%) as a white solid.

¹H-NMR (CDCl₃) δ: 1.75-2.22 (8H, m), 7.44-7.66 (4H, m), 7.70-7.80 (3H,m), 8.13 (1H, m), 8.24 (1H, m), 8.87 (1H, s), 10.61 (1H, s).

Step 3

Compound (50) (100 mg, 0.26 mmol) was dissolved in methanol (1 ml) and 1mol/l aqueous solution of sodium hydroxide (0.31 ml, 0.31 mmol) wasadded, and heated with stirring at 50° C. for 20 minutes. The reactionmixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with water and dried over sodium sulfate. Thesolvent was concentrated under reduced pressure and the resultingresidue was recrystallized from ethyl acetate/n-hexane (1:5) to affordCompound (51) (75 mg, ˜100%) as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 1.70-2.16 (8H, m), 3.80 (2H, br s), 5.55-6.90 (3H, m),7.64 (1H, m), 7.68 (1H, d, J=8.1 Hz), 8.09 (1H, d, J=8.4 Hz), 7.14 (1H,s)

Step 4

Compound (51) (72.9 mg, 0.26 mmol) was dissolved in acetonitrile (2 ml)and dimethyl sulfate (0.025 ml, 0.26 mmol) was added, and heated withstirring at 50° C. for 3 hours. The reaction mixture was allowed to coolto room temperature and di-tert-butyl dicarbonate (57 mg, 0.26 mmol) andtriethylamine (0.036 ml, 0.26 mmol) were added successively, and themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with 2 mol/l hydrochloric acid, an aqueoussolution of sodium hydrogen carbonate and water successively, and driedover sodium sulfate. The solvent was concentrated under reduced pressureto afford Compound (52) (102 mg, 99%) as a colorless oil. Compound (30)was used in the following reaction without purification.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.75-2.20 (8H, m), 2.36 (3H, s), 2.44(2H, s), 7.50 (1H, m), 7.63 (1H, m), 8.12 (1H, m), 9.85 (1H, m)

Step 5

Compound (52) (102 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2ml), methanol (1 ml) and water (0.5 ml) and ammonium chloride (34.7 mg,0.65 mmol) and iron powders (72.4 mg, 1.30 mmol) were added, and heatedto reflux for 2.5 hours. Insoluble material was filtered off and thefiltrate was concentrated under reduced pressure to afford Compound (53)(96 mg, ˜100%) as a pale yellow oil. Compound (31) was used in thefollowing reaction without purification.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.66-2.20 (8H, m), 2.38 (3H, s), 3.34(2H, s), 3.66 (1H, br s), 6.55 (1H, dd, J=2.1, 7.5 Hz), 6.64 (1H, m),6.68 (1H, d, J=7.5 Hz), 7.10 (1H, m), 9.68 (1H, br s).

Step 6

Compound (53) (94 mg, 0.26 mmol) was dissolved in ethyl acetate (2 ml)and 5-cyano picolic acid (monohydrate) (64.5 mg, 0.39 mmol),triethylamine (0.072 ml, 0.52 mmol) and diphenylphospholic chloride(0.054 ml, 0.26 mmol) were added successively, and the mixture wasstirred at room temperature for 15 minutes. The reaction mixture waspoured into ice-water and extracted with ethyl acetate. The organiclayer was washed with an aqueous solution of sodium hydrogen carbonateand water successively, and dried over sodium sulfate. The solvent wasconcentrated under reduced pressure and chromatographed on column withethyl acetate/n-hexane (1:3) as eluent. The eluent was concentratedunder reduced pressure to afford Compound (54) (71 mg, 56%) as colorlessoil.

¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 1.90-2.14 (8H, m), 2.38 (3H, s), 3.40(2H, d, J=3.6 Hz), 7.13 (1H, d, J=7.8 Hz), 7.37 (1H, m), 7.60 (1H, s),7.77 (1H, d, J=8.1 Hz), 8.20 (1H, dd, J=1.8, 8.1 Hz), 8.43 (1H, d, J=8.1Hz), 8.88 (1H, m), 9.72 (1H, br s), 9.86 (1H, s).

Step 7

Compound (54) (71 mg, 0.14 mmol) was dissolved in formic acid (0.5 ml)and stirred at room temperature for 18 hours. The reaction mixture waspoured into ice-water and neutralized with an aqueous solution of sodiumhydrogen carbonate, then extracted with ethyl acetate. The organic layerwas washed with water, dried over sodium sulfate and concentrated underreduced pressure. The residue was recrystallized from ethylacetate/n-hexane (1:3) to afford Compound 29 (15.2 mg, 27%) as a whitepowders.

¹H-NMR (CDCl₃) δ: 1.68-2.12 (8H, m), 2.31 (3H, s), 3.47 (2H, s), 7.15(1H, d, J=7.5 Hz), 7.38 (1H, m), 7.64-7.74 (2H, m), 8.21 (1H, dd, J=1.8,8.1 Hz), 8.44 (1H, d, J=8.1 Hz), 8.91 (1H, d, J=1.8 Hz), 9.89 (1H, s).

Example 9 Synthesis of Compound 32

Step 1

To a solution of Compound (55) (82 mg) in tetrahydrofuran (1 ml) wasadded benzoylisothiocyanate (62 μl) at 0° C. and stirred for 10 minutes.1 mol/l aqueous solution of sodium hydroxide (460 μl) was added theretoand the mixture was stirred at room temperature for 40 minutes, followedby at 50° C. for 50 minutes. Methanol (0.5 ml) was added and the mixturewas stirred for 1 hour. After cooling to room temperature, the mixturewas extracted with ethyl acetate, washed with saturated brine and driedover magnesium sulfate. The solvent was removed under reduced pressureto afford Compound (56) (109 mg).

Step 2

To a solution of Compound (56) (109 mg) in acetonitrile (2 ml) was addeddimethyl sulfate (44 μl) and the mixture was stirred at 50° C. for 2hours. Ethyl acetate and a saturated solution of sodium bicarbonate wereadded thereto and the organic layer was washed with a saturated solutionof sodium bicarbonate and a saturated brine and dried over magnesiumsulfate. The solvent was removed under reduced pressure to affordCompound (57) (122 mg).

Step 3

To a solution of Compound (57) (122 mg) in methanol (1 ml) was addeddi-tert-butyl dicarbonate (115 mg) and the mixture was stirred at roomtemperature overnight. The solvent was removed under reduced pressureand the resulting residue was chromatographed on column to affordCompound (58) (64 mg). ¹H-NMR (CDCl₃) δ: 1.50 (3H, s), 2.01-2.14 (1H, m)2.57 (3H, s), 2.72-3.18 (4H, m), 5.35 (1H, m), 7.39 (1H, d, J=8.4 Hz),8.15 (1H, dd, J=8.4, 2.4 Hz), 8.22 (1H, s), 10.12 (1H, br s).

Step 4

To a solution of Compound (58) in methanol (0.6 ml), tetrahydrofuran(0.2 ml) and water (0.13 ml) were added ammonium chloride (39 mg) andiron (41 mg) and the mixture was stirred at 70° C. for 1.5 hours,Methanol (0.5 ml), tetrahydrofuran (0.5 ml) and iron (41 mg) were addedand the mixture was stirred for additional 20 minutes. Ethyl acetate wasadded and insoluble material was filtered off. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was removed under reduced pressure to afford Compound (59) (56mg).

Step 5

To a solution of Compound (59) in tetrahydrofuran (1 ml) were added4-cyano pyridine-2-carboxylic acid monohydrate (31 mg) and triethylamine(60 μl). Diphenyl phospholic chloride (43 μl) was added at 0° C. and themixture was stirred for 5 minutes. Ethyl acetate was added and themixture was washed with saturated brine and dried over magnesiumsulfate. The solvent was removed under reduced pressure and theresulting residue was chromatographed on column to afford Compound (60)(49 mg).

Step 5

Formic acid (165 μl) was added to Compound (60) (49 mg) and stirred atroom temperature for 4.5 hours. Ethyl acetate was added thereto and themixture was made alkaline with 2 mol/l sodium carbonate. The organiclayer was washed with saturated brine and dried over magnesium sulfate.The solvent was removed under reduced pressure and the resulting residuewas washed with ether to afford Compound 32.

¹H-NMR (CDCl₃) δ: 1.86-1.98 (1H, m), 2.40 (3H, s), 2.60-3.04 (3H, m),5.48 (1H, m), 7.26 (1H, m), 7.70 (2H, m), 8.19 (1H, dd, J=8.1, 2.0 Hz),8.43 (1H, d, J=8.1 Hz), 8.89 (1H, d, J=2.0 Hz), 9.84 (1H, s).

Example 10 Synthesis of Compound 33

Step 1

Compound (61) (0.92 g) was dissolved in dichloromethane (3.2 ml) and 3mol/l cyanogen bromide/dichloromethane solution (1.01 ml) was addeddropwise thereto with stirring under ice-cooling. The mixture wasstirred at the same temperature for 20 minutes, followed by stirring atroom temperature for 2 hours. The precipitated insoluble material wasfiltered off and the filtrate was concentrated under reduced pressure toafford Compound (62) as a crude product.

Step 2

Compound (62) obtained in Step 1 was dissolved in methanol (7.7 ml) and1.37 mol/l hydrogen chloride/methanol solution (2.65 ml) was added withstirring at room temperature. After stirring for 2.5 hours, the solventwas removed under reduced pressure to afford Compound (63) as a crudeproduct.

Step 3

Compound (63) obtained in Step 2 was dissolved in tetrahydrofuran (3.5ml) and di-t-butyl dicarbonate (1.98 g) and triethylamine (1.53 g) wereadded with stirring at room temperature and stirred overnight. Theprecipitated insoluble material was filtered off, the filtrate wasconcentrated under reduced pressure and the residue was chromatographedon silica gel to afford Compound (64) (0.25 g).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 3.88 (3H, s), 4.54 (2H, d, J=6.1 Hz),7.53 (1H, t, J=7.6 Hz), 7.61 (1H, d, J=7.6 Hz), 8.14-8.15 (2H, m), 9.28(1H, br s).

Step 4

Tetrahydrofuran (2 ml), methanol (1 ml) and water (0.5 ml) were added toCompound (64) (0.25 mg). Reduced iron (0.23 g) and ammonium chloride(0.11 g) were added to the mixture at room temperature. The mixture washeated to reflux for 40 minutes and the solvent was removed underreduced pressure. Dichloromethane was added thereto, insoluble materialwas filtered off and the filtrate was concentrated under reducedpressure. The residue was chromatographed on silica gel to affordCompound (65) (0.15 g).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.68 (2H, br), 3.87 (3H, s), 4.34 (2H,d, J=5.9 Hz), 6.58-6.64 (3H, m), 7.11 (1H, t, J=7.5 Hz), 9.04 (1H, brs).

Step 5

To 5-cyano picolic acid monohydrate (0.13 g) were added tetrahydrofuran(1.5 ml), diphenyl chlorophosphate (0.14 g) and triethylamine (0.14 g)with stirring under ice-cooling. The mixture was stirred at the sametemperature for 20 minutes and a solution of Compound (65) (0.15 g) intetrahydrofuran (3 ml) and triethylamine (0.11 g) were added thereto.The mixture was stirred at room temperature for 30 minutes, water andsodium hydrogen carbonate were added thereto and the reaction mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate and thesolvent was removed under reduced pressure to afford Compound (66) as acrude product.

Step 6

Formic acid (1.1 ml) was added to Compound (66) obtained in Step 5 andthe mixture was stirred at room temperature overnight. Ice and asaturated aqueous solution of sodium hydrogen carbonate were added tothe reaction mixture. After the mixture was extracted with chloroform,the organic layer was washed with water and saturated brine and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure and crystallized from ethyl acetate/ether to afford Compound 33(0.10 g) as a white solid.

¹H-NMR (CDCl₃) δ: 3.76 (3H, s), 4.32 (2H, s), 7.15 (1H, d, J=7.9 Hz),7.37 (1H, t, J=7.9 Hz), 7.70 (2H, t, J=8.2 Hz), 8.20 (1H, dd, J=8.2, 2.1Hz), 8.43 (1H, dd, J=8.2, 0.8 Hz), 8.89 (1H, dd, J=2.1, 0.8 Hz), 9.86(1H, s),

Reference Example 1 Synthesis of MeO-pyrazine carboxylic acid-d3 (69)

Step 1

Compound (67) (10 g) was suspended in water (35 ml) and 2 mol/L-aqueoussolution of sodium hydroxide (34.8 ml) was added and the mixture wasstirred at room temperature for 4.5 hours. 2 mol/L-hydrochloric acid(34.8 ml) was added to neutralize and stirred at room temperatureovernight. The precipitated insoluble material was collected byfiltration, washed with water and dried under reduced pressure to affordCompound (68) (3.47 g).

¹H-NMR (DMSO-d₆) δ 8.93 (1H, s), 9.03 (1H, s).

Step 2

Compound (68) (2.5 g) was dissolved in N,N-dimethylformamide (20 ml) andmethanol-D4 (12.8 ml) was added and the mixture was cooled to 0° C.Potassium t-butoxide (7.08 g) was added and the mixture was stirred at50° C. for 3 hours 45 minutes. The mixture was cooled to roomtemperature and water was added to dissolve insoluble material. 2mol/1-hydrochloric acid (27.6 ml) was added and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and the solvent was removed under reduced pressure toafford Compound (69) (1.56 g).

¹H-NMR (DMSO-d₆) δ: 8.39 (1H, s), 8.81 (1H, s), 13.28 (1H, br s).

Example 11 Optical Resolution of Compound 88

Step 3

Compound (88) (about 240 mg) was optically resolved under the followingconditions to afford Compound (100) (110 mg) and Compound (101) (110mg). Chiral column: CHIRALCEL OD-H, size: 5 cm I.D.×25 cmL, mobilephase: n-hexane/ethanol/diethylamine=50/50/0.1, temperature: 40° C.,detection wave length: 313 nM.

Compound 100: m/z 418 [M+1]

Compound 101: m/z 418 [M+1]

Example 12 Synthesis of Compound 97

Step 1

Compound (70) (84.1 mg) was dissolved in ethyl acetate (1.6 ml) and5-CD₃O-pyrazine-2-carboxylic acid (47.6 mg), triethylamine (191 μl), anddiphenyl phosphorochloridate (69 μl) were added at 0° C. and the mixturewas stirred for 45 minutes. Water and ethyl acetate were addedsuccessively, and the organic layer was washed with water and brine anddried over sodium sulfate. The solvent was removed under reducedpressure and the resulting residue was purified by chromatography toafford Compound (71) (106 mg).

¹H NMR (CDCl₃) δ: 1.32 (4H, s), 1.53 (9H, s), 3.82 (3H, s), 6.94-6.98(1H, m), 7.30 (1H, t, J=7.9 Hz), 7.42 (1H, s), 7.66-7.69 (1H, m), 8.16(1H, s), 9.01 (1H, s), 9.33 (1H, s), 9.48 (1H, s).

Step 2

Compound (71) (102 mg) was dissolved in dichloromethane (2.0 ml) andtrifluoroacetic acid (353 μl) was added at room temperature, and themixture was stirred for 2 hours. Water, a saturated aqueous solution ofsodium hydrogen carbonate, chloroform and methanol were added and theorganic layer was washed with water and brine and dried over sodiumsulfate. The solvent was removed under reduced pressure and the obtainedresidue was purified by chromatography to afford Compound 97 (71.9 mg).

¹H-NMR (CDCl₃) δ: 1.17-1.40 (4H, m), 3.76 (3H, s), 4.21 (1H, br s), 5.00(1H, br a), 6.95 (1H, d, J=8.1 Hz), 7.31 (1H, t, J=7.9 Hz), 7.55-7.58(2H, m), 8.15 (1H, d, J=1.2 Hz), 9.01 (1H, d, J=1.2 Hz), 9.48 (1H, s).

Example 13 Synthesis of Compound 98

Step 1

3-nitro benzoyl chloride (13.5 g) was dissolved in dichloromethane (130ml) and anisole (1) (7.22 ml) and aluminium chloride (11.5 g) were addedat room temperature, and the mixture was stirred for 2 hours. Water anddichloromethane were added thereto and the organic layer was washed withbrine and dried over sodium sulfate. The solvent was removed underreduced pressure and diisopropyl ether was added to the resultingresidue. The precipitated solid was collected and purified to affordCompound (18) (12.1 g).

¹H-NMR (CDCl₃) δ: 3.91 (3H, s), 7.00 (2H, dt, J=9.4, 2.4 Hz), 7.69 (1H,t, J=7.9 Hz), 7.81 (2H, dt, J=9.4, 2.4 Hz), 8.07-8.11 (1H, m), 8.40-8.44(1H, m), 8.57 (1H, t, J=1.9 Hz),

Step 2

Compound (18) (5.01 g) was dissolved in tetrahydrofuran (50 ml) and2-methylpropane-2-sulfine amide (3.07 g) and tetraethyl orthotitanate(7.22 ml) were added at room temperature, and the mixture was heated toreflux for 4 hours. Additional 2-methylpropane-2-sulfineamide (1.18 g)and tetraethyl orthotitanate (4.69 ml) were added and the mixture washeated to reflux for 1.5 hours. Brine and ethyl acetate were addedthereto and the mixture was filtered. The filtrated organic layer waswashed with water and brine, dried over magnesium sulfate and thesolvent was removed under reduced pressure. The resulting residue waspurified by chromatography to afford Compound (73) (5.50 g).

¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 3.87 (3H, s), 6.93 (2H, d, J=7.7 Hz),7.57-7.67 (4H, m), 8.18 (1H, br s), 8.34 (1H, dd, J=9.2, 2.1 Hz).

Step 3

Compound (73) (5.46 g) was dissolved in methanol (55 ml), water (22 ml)and tetrahydrofuran (82 ml) and iron (3.68 g) and ammonium chloride(0.88 g) were added at room temperature and the mixture was heated toreflux for 1.5 hours. The reaction mixture was filtered and the solventwas removed under reduced pressure. Water and ethyl acetate were added,the organic layer was washed with water and brine, dried over sodiumsulfate and the solvent was removed under reduced pressure. Theresulting residue was purified by chromatography to afford Compound (74)(4.39 g),

¹H-NMR (CDCl₃) δ: 1.27 (9H, s), 3.78 (2H, s), 3.85 (3H, s), 6.67-6.89(5H, m), 7.21 (1H, t, J=7.5 Hz), 7.71 (2H, br s).

Step 4

Compound (74) (4.32 g) was dissolved in tetrahydrofuran (22 ml) andtriethylamine (2.72 ml) and trifluoroacetic acid anhydride (2.21 ml)were added at 0° C., and the mixture was stirred for 45 minutes. Waterand ethyl acetate were added successively, the organic layer was washedwith water and brine and dried over magnesium sulfate. The solvent wasremoved under reduced pressure and the resulting residue was purified bychromatography to afford Compound (75) (4.69 g).

¹H-NMR (CDCl₃) δ: 1.31 (9H, s), 3.85 (3H, s), 6.89 (2H, d, J=8.5 Hz),7.15 (1H, br s), 7.39 (1H, t, J=7.8 Hz), 7.64 (4H, br s), 9.17 (1H, brs).

Step 5

Methyl magnesium bromide (18.2 ml, 3.0 mol/l solution in ether) wasdissolved in tetrahydrofuran (76 ml) and a solution of Compound (5)(3.87 g) in tetrahydrofuran (38 ml) was added at 0° C. The mixture wasstirred at room temperature for 8 hours. A saturated aqueous solution ofammonium chloride and ethyl acetate were added successively, and theorganic layer was washed with water and brine and dried over sodiumsulfate. The solvent was removed under reduced pressure and theresulting residue was purified by chromatography to afford Compound (76)(1.58 g).

¹H-NMR (CDCl₃) δ: 1.23 (s) and 1.25 (s) (9H), 2.05 (s) and 2.07 (s)(3H), 3.79 (3H, s), 3.84 (1H, s), 6.80-6.87 (2H, m), 7.15-7.24 (4H, m),7.30-7.35 (1H, m), 7.54-7.61 (2H, m), 8.14 (br s) and 8.40 (br s) (1H).

Step 6

Compound (76) (1.50 g) was dissolved in 4 mol/l solution of hydrochloricacid in dioxane (7.0 ml). Methanol (192 μl) was added to the mixture atroom temperature. After stirring for 1 hour, water and ether were addedsuccessively and the aqueous layer was separated. 2 mol/l Aqueoussolution of potassium carbonate and ethyl acetate were added to theaqueous layer and the organic layer was washed with water and brine, anddried over sodium sulfate to afford Compound (77) (1.16 g).

¹H NMR (CDCl₃) δ: 1.84 (3H, s), 3.71-3.81 (5H, m), 6.81-6.87 (2H, m),7.23-7.36 (4H, m), 7.46 (1H, t, J=2.0 Hz), 7.58-7.60 (1H, m), 7.82 (1H,br s).

Step 7

Compound (77) (1.16 g) was dissolved in tetrahydrofuran (12 ml) andbenzoylisothiocyanate (484 μl) was added at 0° C., and the mixture wasstirred at room temperature for 15 minutes. Benzoylisothiocyanate (46μl) was added at 0° C. and the mixture was stirred at room temperaturefor 20 minutes. Methanol (12 ml) and 1 mol/l aqueous solution of sodiumhydroxide (10.3 ml) were added at room temperature and the mixture washeated to reflux for 1.5 hours. Water and ethyl acetate were addedsuccessively, the organic layer was washed with water and brine anddried over sodium sulfate. The solvent was removed under reducedpressure and the resulting residue was purified by chromatography toafford Compound (78) (806 mg).

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 3.74 (2H, s), 3.81 (3H, s), 6.60-6.63(2H, m), 6.68-6.71 (1H, m), 6.86-6.91 (2H, m), 6.94 (1H, s), 7.11-7.17(1H, m), 7.25-7.30 (4H, m).

Step 8

Compound (78) (794 mg) was dissolved in dimethylformamide (22 ml) andmethyl iodide (181 μl) was added at room temperature, and the mixturewas stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added successively, the organic layerwas washed with water and brine and dried over sodium sulfate. Thesolvent was removed under reduced pressure to afford crude mixture ofCompound (79) (1.09 g).

¹H-NMR (CDCl₃) δ: 1.61-1.80 (2H, m), 2.12-2.51 (5H, m), 3.63 (2H, s),3.78 (3H, s), 3.95 (1H, br s), 6.54-6.84 (5H, m), 7.09 (1H, t, J=7.7Hz), 7.25-7.39 (2H, m).

Step 9

The crude mixture of Compound (79) (4.32 g) was dissolved in methanol(10 ml) and 1 mol/l solution of sodium methoxide in methanol (3.95 ml)was added at room temperature and the mixture was stirred for 1 hour.Water and ethyl acetate were added successively, and the organic layerwas washed with water and brine and dried over sodium sulfate. Thesolvent was removed under reduced pressure and the resulting residue waspurified by chromatography to afford Compound (80) (559 mg).

¹H-NMR (CDCl₃) δ: 2.01 (3H, s), 3.68 (2H, s), 3.80 (3H, s), 4.06 (1H, brs), 6.59-6.62 (2H, m), 6.67-6.70 (1H, 6.83-6.88 (2H, m), 7.09-7.15 (1H,m), 7.21-7.26 (2H, m).

Step 10

Compound (80) (542 mg) was dissolved in 2 mol/l solution of hydrochloricacid in methanol (20 ml) and the mixture was stirred at room temperaturefor 1 hour 15 minutes. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added successively, the organic layerwas washed with brine, and dried over sodium sulfate. The solvent wasremoved under reduced pressure and the resulting residue was purified bychromatography to afford Compound (81) (526 mg).

¹H-NMR (DMSO-d₆) δ: 1.63 (s) and 1.79 (s) (3H), 3.43-3.72 (6H, m), 4.50(2H, s), 4.92 (s) and 5.01 (s) (2H), 6.31-6.60 (3H, m), 6.77-6.95 (3H,m), 7.22 (d, J=8.8 Hz) and 7.36 (2d, J=8.8 Hz) (2H).

Step 11

Compound (81) (29.9 mg) was dissolved in methanol (0.6 ml) and 2 mol/laqueous solution of hydrochloric acid (50 μl) was added at roomtemperature, and the mixture was stirred for 10 minutes.5-cyanopyridine-2-carboxylic acid monohydrate (29.9 mg) and WSCD HCl(23.0 mg) were added and the mixture was stirred for 1 hour. A saturatedaqueous solution of sodium hydrogen carbonate and ethyl acetate wereadded successively and the organic layer was washed with brine and driedover sodium sulfate. The solvent was removed under reduced pressure andthe resulting residue was purified by chromatography to afford Compound98 (38.7 mg).

¹H-NMR (DMSO-d_(c)) δ: 1.74 (s) and 1.89 (s) (3H), 3.44 (s) and 4.59 (s)(2H), 3.70-3.73 (6H, m), 6.80-6.89 (2H, m), 7.06-7.38 (4H, m), 7.71 (d,J=6.5 Hz) and 7.81 (d, J=6.5 Hz) (1H), 7.95 (s) and 8.01 (s) (1H), 8.26(1H, d, J=7.9 Hz), 8.56 (1H, dd, J=8.2, 2.1 Hz), 9.17 (1H, s), 10.68 (s)and 10.78 (s) (1H).

Example 14 Synthesis of Compound 99

Step 1

Compound (83) was synthesized from Compound (82) in one step accordingto the method disclosed in a literature (Org. Lett. 2005. 7, 355.).

¹H-NMR (CDCl₃) δ: 1.86 (br s, 2H), 4.55 (br s, 1H), 7.59 (t, J=8.0 Hz,1H), 7.80 (d, J=7.7 Hz, 1H), 8.25 (dq, J=8.2, 1.0 Hz, 1H), 8.35 (s, 1H).

Compound 99 was synthesized from Compound (83) according to theaforementioned procedure for synthesis of Compound g.

¹H-NMR (CDCl₃) δ: 1.55 (d, J=18.8 Hz, 4H), 3.80 (s, 3H), 3.89 (s, 2H),4.58 (q, J=7.3 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H),7.81 (s, 1H), 7.85 (m, 1H), 8.21 (dd, J=8.1, 2.0 Hz, 1H), 8.43 (dd,J=8.2, 0.8 Hz, 1H), 8.90 (dd, J=2.0, 0.9 Hz, 1H), 9.89 (s, 1H).

Example 15 Synthesis of Compound 102

Step 1

3-nitro benzoaldehyde (7.56 g) was dissolved in tetrahydrofuran (100 ml)and a solution of (4-(benzyloxy)phenyl)magnesium bromide intetrahydrofuran (1.0 mol/l, 55 ml) was added at −40° C. over 30 minutes.After warmed to 0° C., the mixture was stirred for 20 minutes. 10%Aqueous solution of citric acid (50 ml) was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the resulting residue waspurified by chromatography to afford Compound (85) (16.77 g).

¹H-NMR (CDCl₃) δ: 2.42 (d, J=3.1 Hz, 1H), 5.06 (s, 3H), 5.88 (br s, 1H),6.92-7.00 (m, 3H), 7.24-7.53 (m, 7H), 7.70 (d, J=7.2 Hz, 1H), 8.11 (d,J=7.5 Hz, 1H), 8.28 (s, 1H).

Step 2

Compound (85) (14.15 g) was dissolved in dichloromethane (100 ml) andtriethylamine (8.8 ml) was added at 0° C., then methane sulfonylchloride (5.80 g) was added over 10 minutes. The mixture was warmed toroom temperature and stirred for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, water and ethyl acetate were addedto the residue and the layers were separated. The organic layer waswashed with a saturated aqueous solution of ammonium chloride, asaturated aqueous solution of sodium hydrogen carbonate and brine anddried over magnesium sulfate. The solvent was removed under reducedpressure, the resulting residue was dissolved in dimethyl formamide (50ml) and sodium azide (3.57 g) was added at room temperature. Thereaction mixture was warmed to 50° C. and stirred for 30 minutes. Waterwas added to the reaction mixture and extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and dried overmagnesium sulfate. The solvent was removed under reduced pressure andthe resulting residue was purified by chromatography to afford Compound(86) (15.21 g).

¹H-NMR (CDCl₃) δ: 5.07 (s, 2H), 5.77 (s, 1H), 6.96-7.02 (m, 2H),7.18-7.24 (m, 2H), 7.30-7.45 (m, 5H), 7.53 (t, J=7.9 Hz, 1H), 7.65 (d,J=7.8 Hz, 1H), 8.13-8.18 (m, 1H), 8.19-8.22 (m, 1H).

Step 3

Compound (86) (9.69 g) was dissolved in tetrahydrofuran (50 ml) andtriphenylphosphine (7.76 g) and water (4.84 g) were added at roomtemperature. The reaction mixture was warmed to 60° C. and stirred for 8hours. The reaction mixture was concentrated under reduced pressure andethyl acetate (100 ml) and 1 mol/l hydrochloric acid (100 ml) were addedto the residue. The resulting precipitate was collected by filtrationand washed with ethyl acetate and water. The obtained solid wasdissolved in a mixture of ethyl acetate (30 ml)-methanol (20 ml)-asaturated aqueous solution of sodium hydrogen carbonate (50 ml) and thelayers were separated. The aqueous layer was extracted with ethylacetate and the organic layers were combined. The combined organic layerwas washed with saturated brine and dried over magnesium sulfate. Thesolvent was removed under reduced pressure to afford Compound (87)(crude yield: 8.99 g).

Step 4

Compound (87) (7.57 g) was dissolved in tetrahydrofuran (50 ml) andbenzoyl isothiocyanate (4.15 g) was added at room temperature, and themixture was stirred for 30 minutes. Methanol (50 ml) and 1 mol/l aqueoussolution of sodium hydroxide (25 ml) were added to the reaction mixtureand the reaction mixture was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure and water wasadded to the residue. The resulting solid was collected by filtration,washed with water and washed under reduced pressure to afford Compound(88) (8.46 g).

¹H-NMR (CDCl₃) δ: 5.10 (s, 2H), 5.82 (s, 2H), 6.67 (d, 2H), 6.97-7.03(m, 2H), 7.17-7.22 (m, 2H), 7.35-7.46 (m, 5H), 7.59 (t, J=7.9 Hz, 1H),7.69 (d, J=7.7 Hz, 1H), 8.16-8.17 (m, 1H), 8.17-8.22 (m, 1H).

Step 5

Compound (88) (2.00 g) was dissolved in dimethylformamide (10 ml) andmethane iodide (0.35 ml) was added at room temperature. The reactionmixture was warmed to 40° C. and stirred for 1.5 hours. A saturatedaqueous solution of sodium hydrogen carbonate was added and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate and the solvent wasremoved under reduced pressure. To the resulting residue was added asolution of sodium methoxide in methanol (1 mol/l, 16.8 ml) at roomtemperature and the mixture was stirred at the same temperature for 3days. Water was added thereto and the mixture was extracted with ethylacetate, the organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was removed under reduced pressureand the resulting residue was partially purified by chromatography toafford Compound (89) (crude yield: 1.99 g).

Step 6

Compound (89) (1.35 g) was dissolved in tetrahydrofuran (10 ml) anddi-tert-butyl dicarbonate (2.00 ml) and triethylamine (1.43 ml) wereadded at room temperature, and the mixture was stirred at the sametemperature for 1 hour. The reaction mixture was concentrated and theresidue was purified by chromatography to afford Compound (90) (1.99 g).

¹H-NMR (CDCl₃) δ: 1.51 (s, 9H), 3.81 (s, 3H), 5.05 (s, 2H), 6.02 (d,J=7.5 Hz, 1H), 6.92-6.98 (m, 2H), 7.11-7.17 (m, 2H), 7.28-7.43 (m, 5H),7.51 (t, J=7.9 Hz, 1H), 7.61 (d, =7.8 Hz, 1H), 8.07-8.15 (m, 2H), 9.49(d, J=7.2 Hz, 1H).

Step 7

Compound (90) (1.18 g) was dissolved in methanol (10 ml) and PtO₂ (500mg) was added. The mixture was stirred under hydrogen atmosphere at roomtemperature for 8 hours. Insoluble material was filtered off throughcelite, the filtrate was concentrated under reduced pressure and theresidue was purified by chromatography to afford Compound (91) (760 mg).

¹H-NMR (CDCl₃) δ: 1.49 (s, 9H), 3.79 (s, 3H), 5.81 (d, J=7.5 Hz, 1H),6.52-6.72 (m, 5H), 6.99-7.13 (m, 3H), 9.30 (d, J=7.6 Hz, 1H).

Step 8

Compound (91) (502 mg) was dissolved in methanol (3 ml), 5-cyanopicoline acid (220 mg) and4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl morpholinium chloride(660 mg) were added at room temperature and the mixture was stirred atthe same temperature for 2 hours. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over magnesium sulfate andthe solvent was removed under reduced pressure. The resulting residuewas purified by chromatography to afford Compound (92) (502 mg).

¹H-NMR (CDCl₃) δ: 1.52 (s, 9H), 3.83 (s, 3H), 5.98 (d, J=6.9 Hz, 1H),6.66 (br s, 1H), 6.77-6.84 (m, 2H), 7.07-7.16 (m, 3H), 7.40 (t, J=7.9Hz, 1H), 7.59 (br s, 1H), 7.81 (d, J=8.2 Hz, 1H), 8.22 (dd, J=8.1, 1.9Hz, 1H), 8.43 (dd, J=8.1, 0.9 Hz, 1H), 8.90-8.93 (m, 1H), 9.41 (d, J=7.6Hz, 1H), 9.91 (s, 1H).

Step 9

Compound (92) (50 mg) was dissolved in dimethylformamide (1 ml),potassium carbonate (21 mg) and methane iodide-D3 (17 mg) were added atroom temperature and the mixture was stirred at the same temperature for90 minutes. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate and the solvent wasremoved under reduced pressure. The resulting residue was purified bychromatography to afford Compound (93) (40 mg).

¹H-NMR (CDCl₃) δ: 1.52 (s, 9H), 3.82 (s, 3H), 5.98 (d, J=7.5 Hz, 1H),6.84-6.88 (m, 2H), 7.08 (d, J=7.3 Hz, 1H), 7.16-7.20 (m, 2H), 7.38 (t,J=7.9 Hz, 1H), 7.51 (br s, 1H), 7.84 (d, J=7.6 Hz, 1H), 8.20 (dd, J=8.2,2.1 Hz, 1H), 8.39-8.45 (m, 1H), 8.86-8.91 (m, 1H), 9.42 (d, J=7.0 Hz,1H), 9.84 (s, 1H),

Step 10

Compound (93) (40 mg) was dissolved in formic acid (1 ml) and stirred at40° C. for 90 minutes. The reaction mixture was concentrated underreduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over magnesium sulfate and the solvent wasremoved under reduced pressure. The resulting residue was purified bychromatography to afford Compound 102 (4 mg).

¹H-NMR (CDCl₃) δ: 3.71 (s, 3H), 5.51 (br s, 1H), 6.81-6.86 (m, 2H), 7.15(d, J=8.2 Hz, 1H), 7.22-7.32 (m, 3H), 7.68 (d, J=8.5 Hz, 1H), 7.94 (brs, 1H), 8.18 (s, 1H), 8.26 (d, J=7.5 Hz, 1H), 8.55-8.60 (m, 1H), 9.18(s, 1H), 10.71 (s, 1H).

The following compounds are synthesized in a similar manner to the aboveExamples.

With respect to LC-MS in the table, the unit of retention time is“minute”, and the measurement conditions were as follows:

(Method A)

column: Xbridge C18 (5 μm, i.d. 4.6×50 mm) (Waters)Flow rate: 3 mL/min.UV detection wavelength: 254 nmMobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1%formic acid-containing acetonitrile solutionGradient: performing linear gradient of 10% to 100% solvent [B] for 3minutes, and keeping 100% solvent [B] for 1 minute

(Method B)

column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)Flow rate: 1.6 mL/min.UV detection wavelength: 254 nmMobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1%formic acid-containing acetonitrile solutionGradient: performing linear gradient of 10% to 100% solvent [B] for 3minutes, and keeping 100% solvent [B] for 1 minute

(Method C)

column: Gemini-NX (5 μm, i.d. 4.6×50 mm) (Phenomenex)Flow rate: 3 mL/min.UV detection wavelength: 254 nmMobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1%formic acid-containing methanol solutionGradient: performing linear gradient of 5% to 100% solvent [B] for 3.5minutes, and keeping 100% solvent [B] for 0.5 minute

TABLE 1 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 1

370 1.10 Method B 2

344 1.01 Method B 3

370 1.30 Method B 4

446 1.57 Method B 5

396 1.40 Method B 6

460 1.65 Method B 7

384 1.45 Method B

TABLE 2 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 8

398 1.49 Method B 9

412 1.58 Method B 10

447 1.16 Method B 11

447 1.46 Method B 12

447 1.09 Method B 13

413 0.90 Method B 14

396 1.33 Method B

TABLE 3 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 15

414 1.37 Method B 16

388 1.26 Method B 17

414 1.23 Method B 18

316 0.88 Method B 19

274 0.50 Method B 20

443 0.93 Method B

TABLE 4 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 21

476 1.52 Method B 22

475 1.50 Method B 23

432 1.27 Method B 24

438 1.27 Method B 25

348 0.98 Method B 26

364 1.16 Method B 27

358 1.12 Method B

TABLE 5 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 28

362 1.16 Method B 29

394 1.44 Method B 30

370 1.17 Method B 31

380 1.27 Method B 32

352 1.18 Method B 33

TABLE 6 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 34

338 1.12 Method A 35

354 0.95 Method A 36

354 0.81 Method A 37

368 0.99 Method A 38

381 0.48 Method A 39

382 1.05 Method A 40

318 0.95 Method B 41

326 0.92 Method B

TABLE 7 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 42

328 1.02 Method B 43

334 1.08 Method B 44

336 1.02 Method B 45

46

354 1.08 Method B 47

360 1.14 Method B 48

386 1.34 Method B 49

388 0.96 Method B

TABLE 8 Com LC/MS LC/MS pound LC/MS Retention Measure- No. Structure m/ztime ment Method 50

404 1.40 Method B 51

404 1.44 Method B 52

53

416 1.34 Method B 54

428 1.33 Method A 55

434 1.32 Method B 56

344 0.92 Method A 57

416 1.36 Method B

TABLE 9 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 58

422 1.39 Method B 59

238 0.39 Method B 60

262 0.72 Method B 61

287 1.28 Method B 62

368 1.26 Method B 63

393 1.61 Method B 64

398 1.33 Method B 65

426 1.33 Method B

TABLE 10 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 66

431 1.10 Method B 67

443 0.94 Method B 68

462 1.55 Method B 69

463 1.55 Method B 70

492 1.47 Method B 71

TABLE 11 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 72

73

74

75

76

77

78

79

TABLE 12 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 80

296 0.90 Method B 81

302 0.94 Method B 82

324 1.09 Method B 83

330 1.11 Method B 84

342 0.94 Method A 85

348 0.99 Method A 86

393 0.40 Method B 87

405 1.23 Method B

TABLE 13 Com- LC/MS LC/MS pound LC/MS Retention Measure- No. Structurem/z time ment Method 88

418 1.47 Method B 89

493 1.53 Method B 90

410 1.38 Method B 91

420 1.48 Method B 92

426 1.54 Method B 93

429 1.64 Method B 94

464 1.72 Method B 95

444 1.06 Method A 96

492 2.30 Method A

TABLE 14 LC/MS LC/MS Compound LC/MS Retention Measurement No. Structurem/z time Method 97

345 0.97 Method A 98

430 1.33 Method A 99

378 1.12 Method B 100

418 1.36 Method B 101

418 1.32 Method B 102

419 1.89 Method C

TABLE 15 Compound No. Structure 103

104

105

106

107

108

109

110

111

112

TABLE 16 Compound No. Structure 113

114

115

116

117

118

119

120

121

122

NMR data of the compounds other than the above Examples 1 to 10 are asfollows:

Compound 14

¹H-NMR (CDCl₃) δ: 1.35-1.39 (4H, m), 1.88-1.90 (3H, m), 2.40 (3H, s),5.04-5.05 (2H, m), 6.99 (1H, d, J=8.11 Hz), 7.29-7.34 (1H, m), 7.51 (1H,s), 7.62 (1H, d, J=8.11 Hz), 8.21 (1H, s), 9.02 (1H, s), 9.48 (1H, s).

Compound 27

¹H-NMR (CD₃OD) δ: 1.66 (d, J=6.9 Hz, 3H), 2.67 (s, 3H), 5.23 (d, J=6.4Hz, 1H), 7.21 (dd, J=10.2, 8.9 Hz, 1H), 7.75 (ddd, J=8.8, 4.5, 2.8 Hz,1H), 7.98 (dd, J=6.8, 2.6 Hz, 1H), 8.35 (dd, J=8.1, 0.9 Hz, 1H), 8.42(dd, J=8.2, 2.0 Hz, 1H), 9.05 (dd, J=2.0, 0.8 Hz, 1H).

Compound 34

¹H-NMR (DMSO-d₆) δ: 0.88 (3H, t, J=7.4 Hz), 1.60-1.65 (2H, m), 4.05 (2H,t, J=6.6 Hz), 4.22 (2H, s), 7.08 (1H, d, J=7.6 Hz), 7.31 (1H, t, J=7.9Hz), 7.73-7.74 (1H, m), 7.87 (1H, s), 8.27 (1H, dd, J=8.1, 0.9 Hz), 8.35(1H, s), 8.57 (1H, dd, J=8.2, 2.1 Hz), 9.19 (1H, dd, J=2.1, 0.9 Hz),10.77 (1H, s). Compound 35

¹H-NMR (CDCl₃) δ: 3.42 (3H, s), 3.65 (2H, t, J=4.5 Hz), 4.30 (4H, s),7.14:7.17 (1H, m), 7.35-7.39 (1H, m), 7.70-7.71 (2H, m), 8.20 (1H, dd,J=8.2, 2.1 Hz), 8.43 (1H, dd, J=8.2, 0.8 Hz), 8.90 (1H, dd, J=2.0, 0.9Hz), 9.86 (1H, s).

Compound 36

¹H-NMR (CDCl₃) δ: 1.81-1.83 (2H, m), 3.61 (2H, t, J=5.6 Hz), 4.29 (2H,s), 4.39 (2H, t, J=5.6 Hz), 7.13 (1H, d, J=7.6 Hz), 7.37 (1H, t, J=7.9Hz), 7.61 (1H, d, J=7.9 Hz), 7.80 (1H, s), 8.20 (1H, dd, J=8.1, 2.0 Hz),8.42 (1H, dd, J=8.1, 0.6 Hz), 8.89 (1H, dd, J=1.8, 0.8 Hz), 9.86 (1H,s).

Compound 37

¹H-NMR (CDCl₃) δ: 1.94-1.96 (2H, m), 3.33 (3H, s), 3.47 (2H, t, J=6.1Hz), 4.16 (2H, s), 4.31 (2H, s), 7.13-7.15 (1H, m), 7.37 (1H, t, J=7.9Hz), 7.69-7.71 (3H, m), 8.20 (1H, dd, J=8.2, 2.1 Hz), 8.43 (1H, dd,J=8.1, 0.8 Hz), 8.89 (1H, dd, J=2.0, 0.6 Hz), 9.85 (1H, s).

Compound 38

¹H-NMR (CDCl₃) δ: 1.84-1.86 (2H, m), 2.19 (6H, s), 2.31 (2H, t, J=7.0Hz), 4.26 (2H, t, J=5.8 Hz), 4.31 (2H, s), 7.09 (1H, d, J=7.6 Hz), 7.32(1H, t, J=7.9 Hz), 7.65 (1H, s), 7.71 (1H, d, J=7.9 Hz), 8.16 (1H, dd,J=8.2, 2.0 Hz), 8.38 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=1.4 Hz), 9.93(1H, s).

Compound 39

¹H-NMR (CDCl₃) δ: 1.71-1.76 (4H, m), 3.29 (3H, s), 3.36 (2H, t, J=6.1Hz), 4.20 (2H, t, J=6.2 Hz), 4.30 (2H, s), 7.10 (1H, d, J=7.8 Hz), 7.33(1H, t, J=7.8 Hz), 7.67-7.70 (2H, m), 8.18 (1H, dd, J=8.1, 2.0 Hz), 8.39(1H, d, J=8.1 Hz), 8.86 (1H, d, J=1.2 Hz), 9.88 (1H, s).

Compound 45

1H-NMR (CDCl₃) δ: 1.31 (s, 4H), 3.95 (s, 3H), 4.07 (s, 3H), 7.01 (d,J=8.5 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.55 (t, J=1.8 Hz, 1H), 7.62 (d,J=8.1 Hz, 1H), 8.16 (d, J=1.3 Hz, 1H), 9.00 (d, J=1.3 Hz, 1H), 9.50 (s,1H).

Compound 52

¹H-NMR (DMSO-d₆) δ: 3.67 (s, 3H), 5.43 (s, 1H), 5.69 (s, 2H), 7.07 (t,J=8.9 Hz, 2H), 7.18-7.27 (m, 2H), 7.44 (dd, J=8.6, 5.9 Hz, 2H), 7.66 (d,J=7.7 Hz, 1H), 7.97 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.56 (dd, J=8.2,2.0 Hz, 1H), 9.17 (d, J=2.0 Hz, 1H), 0.68 (s, 1H).

Compound 71

¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 3.93 (0.5H, s), 4.19 (2.5H, s),7.51-8.25 (8H, m), 8.25 (0.5H, br), 8.99 (0.5H, br), 10.89 (1H, s)

Compound 72

¹H-NMR (CDCl₃) δ: 2.67 (3H, br s), 3.93 (3H, s), 4.46 (2H, br s), 7.28(1H, d, J=8.9 Hz), 7.34 (1H, ddd, J=8.1, 6.6, 1.2 Hz), 7.41 (1H, ddd,J=8.1, 6.6, 1.2 Hz), 7.57 (1H, d, J=8.9 Hz), 7.75 (1H, dd, J=8.1, 1.2Hz), 7.90 (1H, d, J=8.1, 1.2 Hz)

Compound 73

¹H-NMR (CDCl₃) δ: 2.63 (3H, s), 4.48 (2H, br s), 7.42-7.51 (4H, m),7.75-7.89 (2H, m)

Compound 74

¹H-NMR (CDCl₃) δ: 2.53 (3H, s), 2.86 (2H, t, J=6.5 Hz), 3.70 (2H, q,J=6.5 Hz), 4.59 (2H, br s), 6.85-7.21 (4H, m), 8.10 (1H, dd, J=8.1, 2.0Hz), 8.21-8.29 (2H, m), 8.80 (1H, dd, J=2.0, 0.8 Hz)

Compound 75

¹H-NMR (CDCl₃) δ: 4.06 (3H, s), 4.13 (2H, s), 7.03 (1H, dd, J=7.2, 1.0Hz), 7.37 (1H, dd, J=8.2, 7.2 Hz), 7.52 (1H, dd, J=8.2, 1.0 Hz), 7.86(1H, d, J=8.8 Hz), 7.95 (1H, dd, J=8.8, 2.2 Hz), 8.21 (1H, dd, J=8.1,2.0 Hz), 8.37 (1H, d, J=2.2 Hz), 8.47 (1H, dd, J=8.1, 0.9 Hz), 8.92 (1H,dd, J=2.0, 0.9 Hz), 10.02 (1H, s)

Compound 76

¹H-NMR (CDCl₃) δ: 4.05 (3H, s), 4.20 (2H, s), 7.10 (1H, dd, J=7.3, 1.1Hz), 7.59 (1H, dd, J=8.5, 7.3 Hz), 7.78 (1H, dd, J=8.5, 1.1 Hz), 8.23(1H, dd, J=8.2, 2.0 Hz), 8.47 (1H, dd, J=8.2, 0.8 Hz), 8.94 (1H, dd,J=2.0, 0.8 Hz), 8.98 (1H, d, J=2.8 Hz), 9.12 (1H, d, J=2.8 Hz), 10.08(1H, s)

Compound 77

¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 3.92 (2H, s), 4.09 (3H, s), 7.29 (1H, d,J=8.4 Hz), 7.46 (1H, d, J=8.4 Hz), 7.81 (1H, d, J=8.9 Hz), 7.89 (1H, dd,J=8.9, 2.0 Hz), 8.20 (1H, d, J=2.0 Hz), 8.21 (1H, J=8.2, 2.0 Hz), 8.47(1H, dd, J=8.2, 0.9 Hz), 8.92 (1H, dd, J=2.0, 0.9 Hz), 9.99 (1H, s)

Compound 78

¹H-NMR (CDCl₃) δ: 2.65 (3H, br s), 4.66 (2H, br s), 7.10 (1H, dd, J=7.4,1.0 Hz), 7.60 (1H, dd, J=8.4, 7.4 Hz), 7.80 (1H, dd, J=8.4, 1.0 Hz),8.23 (1H, dd, J=8.1, 2.0 Hz), 8.47 (1H, dd, J=8.1, 1.0 Hz), 8.87 (1H, d,J=2.7 Hz), 8.94 (1H, d, J=2.0, 1.0 Hz), 9.14 (1H, d, J=2.7 Hz), 10.08(1H, s)

Compound 79

¹H-NMR (CDCl₃) δ: 2.31 (3H, s), 2.72 (3H, s), 4.38 (2H, s), 7.29 (1H, d,J=8.3 Hz), 7.49 (1H, d, J=8.3 Hz), 7.83 (1H, d, J=8.9 Hz), 7.94 (1H, dd,J=8.9, 2.2 Hz), 8.08 (1H, J=2.2 Hz), 8.21 (1H, J=8.1, 2.0 Hz), 8.48 (1H,dd, J=8.1, 0.9 Hz), 8.94 (1H, dd, J=2.0, 0.9 Hz), 10.00 (1H, s)

Compound 97

¹H-NMR (CDCl₃) δ: 1.17-1.40 (4H, m), 3.76 (3H, s), 4.21 (1H, br s), 5.00(1H, br s), 6.95 (1H, d, J=8.1 Hz), 7.31 (1H, t, J=7.9 Hz), 7.55-7.58(2H, m), 8.15 (1H, d, J=1.2 Hz), 9.01 (1H, d, J=1.2 Hz), 9.48 (1H, s).

Compound 98

¹H-NMR (DMSO-d6) δ: 1.74 (s) and 1.89 (s) (3H), 3.44 (s) and 4.59 (s)(2H), 3.70-3.73 (6H, m), 6.80-6.89 (2H, m), 7.06-7.38 (4H, m), 7.71 (d,J=6.5 Hz) and 7.81 (d, J=6.5 Hz) (1H), 7.95 (s) and 8.01 (s) (1H), 8.26(1H, d, J=7.9 Hz), 8.56 (1H, dd, J=8.2, 2.1 Hz), 9.17 (1H, s), 10.68 (s)and 10.78 (s) (1H).

Compound 102

¹H-NMR (CDCl₃) δ: 3.71 (s, 3H), 5.51 (br s, 1H), 6.81-6.86 (m, 2H), 7.15(d, J=8.2 Hz, 1H), 7.22-7.32 (m, 3H), 7.68 (d, J=8.5 Hz, 1H), 7.94 (brs, 1H), 8.18 (s, 1H), 8.26 (d, J=7.5 Hz, 1H), 8.55-8.60 (m, 1H), 9.18(s, 1H), 10.71 (s, 1H).

The effect of the present invention was confirmed by the following TestExamples.

Test Example 1 Assay of BACE1 Inhibiting Activity

48.5 μL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu:Xεε-amino-n-capronic acid, Eu=Europium cryptate) was added to each wellof 96-hole half-area plate (a black plate: Costar Corporation), andafter addition of 0.5 μl of the test compound (dissolved inN,N′-dimethylformaldehyde) and 1 μl of Recombinant human BACE1 (R&DSystems), the reaction mixture was incubated at 30° C. for 3 hours. Thesubstrate peptide was synthesized by reacting Cryptate TBPCOOH mono SMP(CIS bio international) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute,Inc.). The final concentrations of the substrate peptide and Recombinanthuman BACE1 were adjusted to 18 nM and 7.4 nM respectively, and thereaction was performed in sodium acetate buffer (50 mM sodium acetate,pH 5.0, 0.008% Triton X-100). After the completion of reaction, 50 μl of8.0 μg/ml Streptavidin-XL665 (CIS bio international) dissolved inphosphate buffer (150 mM K₂HPO₄—KH₂PO₄, pH 7.0, 0.008% Triton X-100, 0.8M KF) was added to each well and left stand at 30° C. for an hour. Then,fluorescence intensity was measured (excitation wavelength: 320 nm,measuring wavelength: 620 nm and 665 nm) using Wallac 1420 multilabelcounter (Perkin Elmer life sciences). Enzymatic activity was determinedfrom counting ratio of each wavelength (10,000×Count 665/Count 620) and50% inhibitory concentration against the enzymatic activity wascalculated. IC₅₀ values of the test compounds are indicated in Table 17.

TABLE 17 Compound No. IC50 (μM) 1 3.67 3 0.13 7 1.21 11 0.29 12 0.27 150.14 28 0.79 50 0.188 94 0.032

The following compounds showed the IC₅₀ value of 1 μM or less in thesimilar test.

Compounds 4, 5, 6, 8, 9, 10, 14, 16, 17, 21, 44, 48, 51, 52, 53, 54, 55,57, 58, 68, 70, 75, 77, 79, 88, 91, 92, 93, 95, 96, 97, 98, 101 and 102.

Test Example 2 Measurement of β-Amyloid (Aβ) Production InhibitoryEffect in Cell

Neuroblastoma SH-SY5Y cells (SH/APPwt) with human wild-type β-APPexcessively expressed therein were prepared at 8×10⁵ cells/mL, and 150μl portions thereof were inoculated into each well of a 96-well cultureplate (Falcon). The cells were cultured for 2 hours at 37° C. in a 5%gaseous carbon dioxide incubator. Then, a solution which had beenpreliminarily prepared by adding and suspending the test compound (DMSO(dimethyl sulfoxide) solution) so as to be 2 μl/50 μl medium was addedto the cell sap. Namely, the final DMSO concentration was 1%, and theamount of the cell culture was 200 μl. After the incubation wasperformed for 24 hours from the addition of the test compound, 100 μl ofthe culture supernatant was collected from each fraction. The amount ofthe Aβ in each fraction was measured.

The Ala amount was measured as follows. 10 μl of a homogeneous timeresolved fluorescence (HTRF) measurement reagent (Amyloid β1-40 peptide;IBA Molecular Holding, S.A.) and 10 μl of the culture supernatant wereput into a 384-well half area microplate (black microplate, Costar) andmixed with each other, and then left standing overnight at 4° C. whilethe light was shielded. Then, the fluorescence intensity (excitationwavelength: 337 nm, measurement wavelength: 620 nm and 665 nm) wasmeasured with a Wallac 1420 multilabel counter (Perkin Elmer lifesciences). The Aβ amount was determined from the count rate at eachmeasurement wavelength (10000×Count 665/Count 620), and the amountneeded to inhibit Aβ production by 50% (IC₅₀) was calculated from atleast six different dosages. Table 18 shows the IC₅₀ value of each testcompound.

TABLE 18 Compound No. IC₅₀ (μM) 1 0.055 2 0.100 3 0.005 4 0.119 5 0.1606 0.172 7 0.082 8 0.040 9 0.061 11 0.524 12 0.036 15 0.004 28 0.193 320.260 45 0.028 58 0.018 88 0.024

The following compounds showed the IC₅₀ value of 1 μM or less in thesimilar test.

Compounds 10, 14, 16, 17, 21, 22, 23, 24, 26, 27, 31, 33, 34, 35, 36,37, 38, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57,64, 68, 70, 75, 77, 79, 82, 83, 84, 85, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, 100, 101 and 102.

Test Example 3 Lowering Effect on Brain β Amyloid in Rats

A test compound is suspended in 0.5% methylcellulose, the finalconcentration is adjusted to 2 mg/mL, and this is orally administered tomale Crj:SD rat (7 to 9 week old) at 10 mg/kg. In a vehicle controlgroup, only 0.5% methylcellulose is administered, and an administrationtest is performed at 3 to 8 animals per group. A brain is isolated 3hours after administration, a cerebral hemisphere is isolated, a weightthereof is measured, the hemisphere is rapidly frozen in liquidnitrogen, and stored at −80° C. until extraction date. The frozencerebral hemisphere is transferred to a homogenizer made of Teflon(registered trade mark) under ice cooling, a 5-fold volume of a weightof an extraction buffer (containing 1% CHAPS({3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate}), 20 mMTris-HCl (pH 8.0), 150 mM NaCl, Complete (Roche) protease inhibitor) isadded, up and down movement is repeated, and this is homogenized tosolubilize for 2 minutes. The suspension is transferred to acentrifugation tube, allowed to stand on an ice for 3 hours or more and,thereafter centrifuged at 100,000×g and 4° C. for 20 minutes. Aftercentrifugation, the supernatant is transferred to an ELISA plate (Wako,product No. 294-62501) for measuring β amyloid 40. ELISA measurement isperformed according to the attached instructions. The lowering effect iscalculated as a ratio compared to the brain p amyloid 40 level ofvehicle control group of each test.

Test Example 4 CYP3A4 Fluorescent MBI Test

The CYP3A4 fluorescent MBI test is a test to examine enhancement ofCYP3A4 inhibition by metabolic reaction of the compound. Here, E.coli-expressing CYP3A4 was used as an enzyme, and a reaction wherein7-benzyloxy trifluoromethylcumarin (BFC) was debenzylated by the CYP3A4enzyme into a fluorescent metabolite 7-hydroxytrifluoromethylcumarin(HFC) was employed as an indicator reaction. The reaction conditionswere as follows.

Substrate: 5.6 μM/L 7-BFC

Pre-reaction time: 0 or 30 minutes

Reaction time: 15 minutes

Reaction temperature: 25° C. (room temperature)

CYP3A4 content (E. coli-expressing enzyme): 62.5 pmol/mL atpre-reaction, 6.25 pmol/mL at reaction (10-fold diluted)

Test compound concentration: 0.625, 1.25, 2.5, 5, 10, and 20 μM (sixdifferent concentrations).

The enzyme and a test compound solution were added to a K-Pi buffer (pH7.4) in the aforementioned amounts for the pre-reaction so that apre-reaction solution was prepared, and this solution was put into a96-well microplate. Part of this solution was transferred to another96-well microplate such that it was diluted with the substrate and theK-Pi buffer to get a 10-fold diluted solution. NADPH, which is acoenzyme, was added so as to trigger the indicator reaction (withoutpre-reaction). As the reaction proceeded for a predetermined timeperiod, acetonitrile/0.5 M Tris (tris hydroxyaminomethane)=4/1 was addedto terminate the reaction. NADPH was also added to the residualpre-reaction solution so as to trigger the pre-reaction (withpre-reaction). As the pre-reaction proceeded for a predetermined timeperiod, part of the solution was transferred to another microplate sothat the solution was diluted with the substrate and the K-Pi buffer toget a 10-fold diluted solution, and then the indicator reaction wastriggered. As the reaction proceeded for a predetermined time period,acetonitrile/0.5 M Tris (tris hydroxyaminomethane)=4/1 was added so asto terminate the reaction. With respect to each of the microplates onwhich the indicator reaction was performed, the fluorescence value ofthe metabolite 7-HFC was measured with a fluorescence plate reader(Ex=420 nm, Em=535 nm).

Control (100%) was prepared by adding only DMSO, which was used as asolvent to dissolve the drug, to the reaction system. The remainingactivity (%) at each concentration after adding the test compoundsolution was calculated, and the IC₅₀ values of without pre reaction andwith pre reaction were calculated by the formula:y=A+((B−A)/(1+((C/x)^(D)))) using XLfit. The IC₅₀ shift value wascalculated by the formula: (the IC₅₀ value of without pre reaction)−(theIC₅₀ value of with pre reaction). The IC₅₀ shift values of the testcompounds are shown in Table 19.

TABLE 19 Compound No. IC50 shift (μM) 1 0 2 0 3 0 4 1 5 −2 6 −2 7 <−2 8−4 9 −5 11 −2 12 <−2 15 <−3 18 0 28 1 30 0 32 0

Test Example 5 hERG Test

As risk assessment for QT prolongation in vitro, the action on delayedrectifier potassium current was studied using a HEK293 cell with a humandelayed potassium ether-a-go-go related gene (hERG) channel expressedtherein.

A cell was maintained at a membrane potential of −80 mV, then +50 mV ofa depolarizing stimulus (2 seconds) was applied to the cell, further −50mV of a repolarizing stimulus (2 seconds) was applied thereto and theinduced peak tail current was measured by a whole-cell patch clamptechnique. 5 μM of the test compounds was applied to the cells for 7minutes, the inhibition rate before application of the test compound wascalculated, and it was compared to the rate of vehicle group (0.5%dimethylsulfoxide solution). The inhibition rate of the test compoundsare shown in Table 20.

TABLE 20 Compound No. Inhibition Rate (%) 1 63.8 3 67.6 15 31.5 18 10.828 60.4 30 14.1 38 8.4 45 2.5

Test Example 6 Ames Test

Ames test was conducted by using TA1537 as strain without metabolicactivation conditions in the pre-incubation method. The test showed thefollowing compounds were detected as negative.

Compounds 1, 2, 3 and 18. Test Example 7 CYP Inhibition Test

Using commercially available pooled human hepatic microsome, andemploying, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2),tolbutamide methyl-hydroxylation (CYP2C9), mephenyloin 4′-hydroxylation(CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedinehydroxylation as typical substrate metabolism reactions of human mainfive CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitorydegree of each metabolite production amount by a test compound wasassessed.

The reaction conditions were as follows:

Substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide(CYP2C9), 50 μmol/L S-mephenitoin (CYP2C19), 5 μmol/L dextromethorphan(CYP2D6), 1 mon terfenedine (CYP3A4); Reaction time, 15 minutes;Reaction temperature, 37° C.; Enzyme, pooled human hepatic microsome 0.2mg protein/mL; Test drug concentration, 1, 5, 10, 20 μmol/L (fourpoints).

Each five kinds of substrates, human hepatic microsome, or a test drugin 50 mM Hepes buffer as a reaction solution was added to a 96-wellplate at the composition as described above, NADPH, a cofactor, wasadded to initiate metabolism reactions as markers and, after theincubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v)solution was added to stop the reaction. After the centrifugation at3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in thesupernatant was quantified by a fluorescent multilabel counter andtributamide hydroxide (CYP2CP metabolite), mephenyloin 4′ hydroxide(CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), andterfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

Addition of only DMSO being a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solutionand IC₅₀ was calculated by reverse presumption by a logistic model usinga concentration and an inhibition rate.

(Result)

Compound 36: five kinds>20 μMCompound 41: five kinds>20 μM

Test Example 7 FAT Test

Each 20 μL of freeze-stored Salmonella typhimurium (TA98 and TA100strain) was inoculated in 10 mL of liquid nutrient medium (2.5% Oxoidnutrient broth No. 2), and the cultures were incubated at 37° C. undershaking for 10 hours. 9 mL of TA98 culture was centrifuged (2000×g, 10minutes) to remove medium, and the bacteria was suspended in 9 mL ofMicro F buffer (K₂HPO₄: 3.5 g/L, KH₂PO₄: 1 g/L, (NH₄)₂SO₄: 1 g/L,trisodium citrate dehydrate: 0.25 g/L, MgSO₄.7H₂O: 0.1 g/L), and thesuspension was added to 110 mL of Exposure medium (Micro F buffercontaining Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL).3.16 mL of TA100 culture was added to 120 mL of Exposure medium toprepare the test bacterial solution. 588 μL of the test bacterialsolution (or mixed solution of 498 ml of the test bacterial solution and90 μL of the S9 mix in the case with metabolic activation system) weremixed with each 12 μL of the following solution: DMSO solution of thetest substance (eight dose levels from maximum dose 50 mg/mL at 2-foldratio); DMSO as negative control; 50 μg/mL of 4-nitroquinoline-1-oxideDMSO solution as positive control for TA98 without metabolic activationsystem; 0.25 μg/mL of 2-(furyl)-3-(5-nitro-2-furyl)acrylamide DMSOsolution as positive control for TA100 without metabolic activationsystem; 40 μg/mL of 2-aminoanthracene DMSO solution as positive controlfor TA98 with metabolic activation system; or 20 μg/mL of2-aminoanthracene DMSO solution as positive control for TA100 withmetabolic activation system. 12 μL of the solution and 688 μL of thetest bacterial solution (a mixed solution of 498 μl of the testbacterial solution and 90 μL of S9 mix with metabolic activationcondition) were mixed and incubated at 37° C. under shaking for 90minutes, 460 μL of the bacterial solution exposed to the test substancewas mixed with 2300 μL of Indicator medium (Micro F buffer containingbiotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo CresolPurple: 37.5 μg/mL), each 50 μL was dispensed into 48 wells per dose inthe microwell plates, and was subjected to stationary cultivation at 37°C. for 3 days. A well containing the bacteria, which has obtained theability of proliferation by mutation in the gene coding amino acid(histidine) synthetase, turns the color from purple to yellow due to pHchange. The number of the yellow wells among the 48 total wells per dosewas counted, and evaluated the mutagenicity by comparing with thenegative control group. (−) means that mutagenicity is negative and (+)means positive.

(Result)

Compound 44 (−)

Test Example 8 Solubility Test

A 2-fold dilution series (12 points) of a 10 mM solution of a testcompound in DMSO was added to a medium (JP-I, JP-II) (2%), andsolubility was assessed by 3 stages (High; >40 μM, Medium; 3-40 μM, Low;<3 μM) from a turbidity after 4 hours (crystallization information).

(Result) Compound 28 High (JP-I) Compound 31 High (JP-I) Compound 40High (JP-I) Compound 45 High (JP-I) Compound 76 High (JP-I) Test Example8(2) Solubility Test

The solubility of each compound is determined under 1% DMSO additionconditions. A 10 mM solution of the compound is prepared with DMSO, and6 μL, of the compound solution is added to 594 μL of an artificialintestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent are addedto 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach1000 mL) with a pH of 6.8. The mixture is left standing for 16 hours at25° C., and the mixture is vacuum-filtered. The filtrate is two-folddiluted with methanol/water=1/1, and the compound concentration in thefiltrate is measured with HPLC or LC/MS/MS by the absolute calibrationmethod.

Test Example 9 Metabolic Stability Test

The target compound was reacted with commercially available pooled humanliver microsomes for a predetermined time period. The residual rate wascalculated by comparing the reacted sample and unreacted sample, andthus the degree of metabolism in liver was evaluated.

In 0.2 mL of a buffer (50 mmol/L tris-HCl pH 7.4, 150 mmol/L potassiumchloride, 10 mmol/L magnesium chloride) containing human livermicrosomes 0.5 mg protein/mL, reaction was carried out in the presenceof 1 mmol/L NADPH for 0 minute or 30 minutes at 37° C. (oxidativereaction). After the reaction, 50 μL of the reaction solution was addedto and mixed with 100 μL of a solution of methanol/acetonitrile=1/1(v/v), and the mixture was centrifuged for 15 minutes at 3000 rpm. Thetest compound in the centrifuged supernatant was quantified by LC/MS/MS,and the residual amount of the test compound after the reaction wascalculated based on the compound amount at O-minute reaction set as100%.

(Results).

Compound 50  100% Compound 76 98.9%

Test Example 9 Powder Solubility Test

Appropriate amounts of the test substances are put into appropriatecontainers. To the respective containers are added 200 μL of JP-1 fluid(sodium chloride 2.0 g, hydrochloric acid 7.0 mL and water to reach 1000mL), 200 μL of JP-2 fluid (phosphate buffer (pH 6.8) 500 mL and water500 mL), and 200 μL of 20 mmol/L TCA (sodium taurocholate)/JP-2 fluid(TCA 1.08 g and water to reach 100 mL). In the case that the testcompound is dissolved after the addition of the test fluid, the bulkpowder is added as appropriate. The containers are sealed, and shakenfor 1 hour at 37° C. The mixtures are filtered, and 100 μL, of methanolis added to each of the filtrate (100 μL) so that the filtrates aretwo-fold diluted. The dilution ratio may be changed if necessary. Thedilutions are observed for bubbles and precipitates, and then thecontainers are sealed and shaken. Quantification is performed by HPLCwith an absolute calibration method.

Test Example 11 BA Test

Materials and methods for studies on oral absorption

(1) Animal: SD rats

(2) Breeding conditions: rats were allowed to freely take solid feed andsterilized tap water

(3) Dose and grouping: orally or intravenously administered at apredetermined dose; grouping was as follows (Dose depends on thecompound)

Oral administration: 1 to 30 mg/kg (n=2 to 3)

Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of dosing solution: for oral administration, in asolution or a suspension state; for intravenous administration, in asolubilized state

(5) Administration method: in oral administration, forcedly administerinto ventriculus with oral probe; in intravenous administration,administer from caudal vein with a needle-equipped syringe

(6) Evaluation items: blood was collected over time, and the plasmaconcentration of drug was measured by LC/MS/MS

(7) Statistical analysis: regarding the transition of the plasmaconcentration, the area under the plasma concentration-time curve (AUC)was calculated by non-linear least squares program WinNonlin (Registeredtrademark), and the bioavailability (BA) was calculated from the AUCs ofthe oral administration group and intravenous administration group

(Result) Compound 48: 87.2% Compound 77: 75.0% Preparation Example 1

A granule containing the following ingredients is produced.

Ingredient Compound represented by the formula (I)  10 mg Lactose 700 mgCorn starch 274 mg HPC-L  16 mg 1000 mg 

The compound represented by the formula (I) and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve.These are mixed with a V-type mixer. To the mixed powder is added aHPC-L (low viscosity hydroxypropylcellulose) aqueous solution, this iskneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm),and dried. The resulting dry granule is passed through a vibration sieve(12/60 mesh) to obtain a granule.

Preparation Example 2

A granule for filling a capsule containing the following ingredients isproduced.

Ingredient Compound represented by the formula (I) 15 mg Lactose 90 mgCorn starch 42 mg HPC-L  3 mg 150 mg 

The compound represented by the formula (I), and lactose are passedthrough a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve.These are mixed, a HPC-L solution is added to the mixed powder, this iskneaded, granulated, and dried. The resulting dry granule is adjusted ina size, and 150 mg of it is filled into a No. 4 hard gelatin capsule.

Preparation Example 3

A tablet containing the following ingredients is produced.

Ingredient Compound represented by the formula (I) 10 mg Lactose 90 mgMicrocrystalline cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg150 mg 

The compound represented by the formula (I), lactose, microcrystallinecellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passedthrough a 60 mesh sieve, and mixed. Magnesium stearate is mixed into themixed powder to obtain a mixed powder for tabletting. The present mixedpowder is directly compressed to obtain a 150 mg of a tablet.

Preparation Example 4

The following ingredients are warmed, mixed, and sterilized to obtain aninjectable.

Ingredient Compound represented by the formula (I)  3 mg Nonionicsurfactant 16 mg Purified water for injection  1 ml

INDUSTRIAL APPLICABILITY

The compound of the present application can be a useful therapeuticagent for diseases induced by production, secretion, and/or depositionof amyloid-β proteins.

1. A compound of formula (I):

wherein X is an oxygen atom or a sulfur atom, ring A is a carbocycle ora heterocycle, (1) when X is an oxygen atom, R¹ is substituted amino,provided that substituted amino is not imino(phenoxy)methylamino orimino Clower alkoxy)methylamino; substituted or unsubstituted mercapto;substituted or unsubstituted carbocyclyl; or substituted orunsubstituted heterocyclyl; and R¹ may be hydrogen when ring A isnaphthalene, (2) when X is a sulfur atom, R¹ is substituted orunsubstituted acylamino, provided that substituted or unsubstitutedacylamino is not unsubstituted acetylamino or unsubstitutedbenzoylamino; substituted or unsubstituted halogenosulfonylamino;substituted or unsubstituted lower alkylsulfonylamino; substituted orunsubstituted lower alkenylsulfonylamino; substituted or unsubstitutedlower alkynylsulfonylamino; substituted or unsubstitutedacylsulfonylamino; substituted or unsubstitutedcarbocyclylsulfonylamino; substituted or unsubstitutedheterocyclylsulfonylamino; substituted or unsubstituted mercapto;substituted or unsubstituted carbocyclyl; or substituted orunsubstituted heterocyclyl, provided that substituted or unsubstitutedheterocyclyl is not thiazolyl substituted with unsubstitutedacetylamine; and R¹ may be hydrogen when ring A is naphthalene, R² ishalogen, substituted or unsubstituted hydroxy, substituted orunsubstituted mercapto, substituted or unsubstituted amino, substitutedor unsubstituted lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkynyl, substituted orunsubstituted acyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl, R³ is substituted orunsubstituted lower alkyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted lower alkynyl, substituted or unsubstitutedcarbocyclyl, or substituted or unsubstituted heterocyclyl, R^(A) andR^(B) are each independently hydrogen, halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted acyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, or R^(A) and R^(B) taken together may formoxo, or R^(A) and R^(B) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle, R^(C) and R^(D) are eachindependently hydrogen, halogen, substituted or unsubstituted hydroxy,substituted or unsubstituted mercapto, substituted or unsubstitutedamino, substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted acyl, substituted or unsubstitutedcarbocyclyl, or substituted or unsubstituted heterocyclyl, or R^(C) andR^(D) together with the carbon atom to which they are attached may forma substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle, m is an integer of 0 to 2, n is an integer of0 to 4, and p is an integer of 0 to 2, its pharmaceutically acceptablesalt, or a solvate thereof.
 2. The compound according to claim 1 wherein(1) when X is an oxygen atom, R¹ is substituted amino, provided thatsubstituted amino is not imino(phenoxy)methylamino or imino(loweralkoxy)methylamino; substituted or unsubstituted mercapto; substitutedor unsubstituted cycloalkyl; substituted or unsubstituted aryl; orsubstituted or unsubstituted heterocyclyl; and (2) when X is a sulfuratom, R¹ is substituted or unsubstituted acylamino, provided thatsubstituted or unsubstituted acylamino is not unsubstituted acetylaminoor unsubstituted benzoylamino; substituted or unsubstitutedhalogenosulfonylamino; substituted or unsubstituted loweralkylsulfonylamino; substituted or unsubstituted loweralkenylsulfonylamino; substituted or unsubstituted loweralkynylsulfonylamino; substituted or unsubstituted acylsulfonylamino;substituted or unsubstituted carbocyclylsulfonylamino; substituted orunsubstituted heterocyclylsulfonylamino; substituted or unsubstitutedmercapto; substituted or unsubstituted cycloalkyl; substituted orunsubstituted aryl; or substituted or unsubstituted heterocyclyl,provided that substituted or unsubstituted heterocyclyl is not thiazolylsubstituted with unsubstituted acetylamino; its pharmaceuticallyacceptable salt, or a solvate thereof.
 3. The compound according toclaim 1 or 2 wherein ring A is an aromatic carbocycle or an aromaticheterocycle, m is an integer of 0, R¹ is substituted or unsubstitutedacylamino, provided that when X is a sulfur atom, then substituted orunsubstituted acylamino is not unsubstituted acetylamino orunsubstituted benzoylamino; and R² is halogen, substituted orunsubstituted hydroxy, substituted or unsubstituted mercapto,substituted or unsubstituted amino, substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted acyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, its pharmaceutically acceptable salt or asolvate thereof.
 4. The compound according to claim 1 wherein X is anoxygen atom, its pharmaceutically acceptable salt or a solvate thereof.5. The compound according to claim 1 wherein X is a sulfur atom, itspharmaceutically acceptable salt or a solvate thereof.
 6. The compoundaccording to claim 1 wherein (i) ring A is a monocycle and p is 1 or 2,or (ii) ring A is a fused ring and p is 0, its pharmaceuticallyacceptable salt or a solvate thereof.
 7. The compound according to claim1 wherein ring A is a benzene ring or a benzene ring fused with anotherring, its pharmaceutically acceptable salt or a solvate thereof.
 8. Thecompound according to claim 1 wherein R¹ is substituted or unsubstitutedacylamino, provided that when X is a sulfur atom, then substituted orunsubstituted acylamino is not unsubstituted acetylamino orunsubstituted benzoyl amino; substituted or unsubstitutedhalogenosulfonylamino; substituted or unsubstituted loweralkylsulfonylamino; substituted or unsubstituted loweralkenylsulfonylamino; substituted or unsubstituted loweralkynylsulfonylamino; substituted or unsubstituted acylsulfonylamino;substituted or unsubstituted carbocyclylsulfonylamino; substituted orunsubstituted heterocyclylsulfonylamino; or substituted or unsubstitutedaryl; its pharmaceutically acceptable salt or a solvate thereof.
 9. Thecompound according to claim 1 wherein R¹ is substituted or unsubstitutedacylamino, provided that when X is a sulfur atom, then “substituted orunsubstituted acylamino” is not unsubstituted acetylamino orunsubstituted benzoylamino; or substituted or unsubstituted loweralkylsulfonylamino; its pharmaceutically acceptable salt or a solvatethereof.
 10. The compound according to claim 1 wherein m is an integerof 0, its pharmaceutically acceptable salt or a solvate thereof.
 11. Thecompound according to claim 1 wherein R² is halogen and n is an integerof 0 or 1, its pharmaceutically acceptable salt or a solvate thereof.12. The compound according to claim 1 wherein R³ is substituted orunsubstituted lower alkyl or substituted or unsubstituted lower alkenyl,its pharmaceutically acceptable salt or a solvate thereof.
 13. Thecompound according to claim 1 wherein R^(C) and R^(D) are eachindependently hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheterocyclyl, or Rc and R^(D) together with the carbon atom to whichthey are attached may form a substituted or unsubstituted carbocycle,and p is an integer of 1, its pharmaceutically acceptable salt or asolvate thereof.
 14. A compound of formula (II):

wherein ring A is a carbocycle or a heterocycle, R⁵ is hydrogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted lower alkynyl or substitutedor unsubstituted acyl, R⁴ is substituted or unsubstituted lower alkyl,provided that when X is a sulfur atom, then substituted or unsubstitutedlower alkyl is not unsubstituted methyl; substituted or unsubstitutedlower alkenyl; a substituted or unsubstituted carbocycle, provided thatwhen X is a sulfur atom, then a substituted or unsubstituted carbocycleis not unsubstituted phenyl; or a substituted or unsubstitutedheterocycle; R² is halogen, substituted or unsubstituted hydroxy,substituted or unsubstituted mercapto, substituted or unsubstitutedamino, substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted acyl, substituted or unsubstitutedcarbocyclyl or substituted or unsubstituted heterocyclyl, R³ issubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted lower alkynyl, substitutedor unsubstituted carbocyclyl or substituted or unsubstitutedheterocyclyl, R^(C) and R^(D) are each independently hydrogen, halogen,substituted or unsubstituted hydroxy, substituted or unsubstitutedmercapto, substituted or unsubstituted amino, substituted orunsubstituted lower alkyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted lower alkynyl, substituted or unsubstitutedacyl, substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, or R^(C) and R^(D) together with the carbonatom to which they are attached may form a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle, n is aninteger of 0 to 4, and p is an integer of 0 to 2, its pharmaceuticallyacceptable salt or a solvate thereof.
 15. The compound according toclaim 14 wherein R⁴ is a substituted or unsubstituted aromaticheterocycle or a substituted or unsubstituted aromatic carbocycle, itspharmaceutically acceptable salt or a solvate thereof.
 16. The compoundaccording to claim 14 wherein ring A is a monocycle, and R⁴ is asubstituted or unsubstituted nitrogen-containing heterocycle, itspharmaceutically acceptable salt or a solvate thereof.
 17. Apharmaceutical composition comprising the compound according claim 1,its pharmaceutically acceptable salt or a solvate thereof.
 18. Apharmaceutical composition having BACE1 inhibitory activity comprisingthe compound according to claim 1, its pharmaceutically acceptable saltor a solvate thereof.
 19. A pharmaceutical composition having amyloid βproduction inhibitory activity comprising the compound according toclaim 1, its pharmaceutically acceptable salt or a solvate thereof. 20.A method for inhibiting BACE1 activity comprising administering thecompound according to claim 1, its pharmaceutically acceptable salt or asolvate thereof.
 21. A compound according to claim 1, itspharmaceutically acceptable salt or a solvate thereof for use in amethod for inhibiting BACE1 activity.
 22. A method for inhibitingamyloid β production comprising administering the compound according toclaim 1, its pharmaceutically acceptable salt or a solvate thereof. 23.A compound according to claim 1, its pharmaceutically acceptable salt ora solvate thereof for use in a method for inhibiting amyloid βproduction.
 24. A pharmaceutical composition comprising the compoundaccording to claim 14, its pharmaceutically acceptable salt or a solvatethereof.
 25. A pharmaceutical composition having BACE1 inhibitoryactivity comprising the compound according to claim 14, itspharmaceutically acceptable salt or a solvate thereof.
 26. Apharmaceutical composition having amyloid β production inhibitoryactivity comprising the compound according to claim 14, itspharmaceutically acceptable salt or a solvate thereof.
 27. A method forinhibiting BACE1 activity comprising administering the compoundaccording to claim 14, its pharmaceutically acceptable salt or a solvatethereof.
 28. A compound according to claim 14, its pharmaceuticallyacceptable salt or a solvate thereof for use in a method for inhibitingBACE1 activity.
 29. A method for inhibiting amyloid β productioncomprising administering the compound according to claim 14, itspharmaceutically acceptable salt or a solvate thereof.
 30. A compoundaccording to claim 14, its pharmaceutically acceptable salt or a solvatethereof for use in a method for inhibiting amyloid β production.